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Sample records for conserved early innate

  1. Analysis of evolutionarily conserved innate immune components in coral links immunity and symbiosis.

    PubMed

    Kvennefors, E Charlotte E; Leggat, William; Kerr, Caroline C; Ainsworth, Tracy D; Hoegh-Guldberg, Ove; Barnes, Andrew C

    2010-11-01

    Reef-building corals are representatives of one of the earliest diverging metazoan lineages and are experiencing increases in bleaching events (breakdown of the coral-Symbiodinium symbiosis) and disease outbreaks. The present study investigates the roles of two pattern recognition proteins, the mannose binding lectin Millectin and a complement factor C3-like protein (C3-Am), in the coral Acropora millepora. The results indicate that the innate immune functions of these molecules are conserved and arose early in evolution. C3-Am is expressed in response to injury, and may function as an opsonin. In contrast, Millectin expression is up-regulated in response to lipopolysaccharide and peptidoglycan. These observations, coupled with localization of Millectin in nematocysts in epidermal tissue, and reported binding of pathogens, are consistent with a key role for the lectin in innate immunity. Furthermore, Millectin was consistently detected binding to the symbiont Symbiodinium in vivo, indicating that the Millectin function of recognition and binding of non-self-entities may have been co-opted from an ancient innate immune system into a role in symbiosis.

  2. B cells enhance early innate immune responses during bacterial sepsis

    PubMed Central

    Kelly-Scumpia, Kindra M.; Scumpia, Philip O.; Weinstein, Jason S.; Delano, Matthew J.; Cuenca, Alex G.; Nacionales, Dina C.; Wynn, James L.; Lee, Pui Y.; Kumagai, Yutaro; Efron, Philip A.; Akira, Shizuo; Wasserfall, Clive; Atkinson, Mark A.

    2011-01-01

    Microbes activate pattern recognition receptors to initiate adaptive immunity. T cells affect early innate inflammatory responses to viral infection, but both activation and suppression have been demonstrated. We identify a novel role for B cells in the early innate immune response during bacterial sepsis. We demonstrate that Rag1−/− mice display deficient early inflammatory responses and reduced survival during sepsis. Interestingly, B cell–deficient or anti-CD20 B cell–depleted mice, but not α/β T cell–deficient mice, display decreased inflammatory cytokine and chemokine production and reduced survival after sepsis. Both treatment of B cell–deficient mice with serum from wild-type (WT) mice and repletion of Rag1−/− mice with B cells improves sepsis survival, suggesting antibody-independent and antibody-dependent roles for B cells in the outcome to sepsis. During sepsis, marginal zone and follicular B cells are activated through type I interferon (IFN-I) receptor (IFN-α/β receptor [IFNAR]), and repleting Rag1−/− mice with WT, but not IFNAR−/−, B cells improves IFN-I–dependent and –independent early cytokine responses. Repleting B cell–deficient mice with the IFN-I–dependent chemokine, CXCL10 was also sufficient to improve sepsis survival. This study identifies a novel role for IFN-I–activated B cells in protective early innate immune responses during bacterial sepsis. PMID:21746813

  3. The Conserved Coronavirus Macrodomain Promotes Virulence and Suppresses the Innate Immune Response during Severe Acute Respiratory Syndrome Coronavirus Infection

    PubMed Central

    Fehr, Anthony R.; Channappanavar, Rudragouda; Jankevicius, Gytis; Fett, Craig; Zhao, Jincun; Athmer, Jeremiah; Meyerholz, David K.; Ahel, Ivan

    2016-01-01

    ABSTRACT ADP-ribosylation is a common posttranslational modification that may have antiviral properties and impact innate immunity. To regulate this activity, macrodomain proteins enzymatically remove covalently attached ADP-ribose from protein targets. All members of the Coronavirinae, a subfamily of positive-sense RNA viruses, contain a highly conserved macrodomain within nonstructural protein 3 (nsp3). However, its function or targets during infection remain unknown. We identified several macrodomain mutations that greatly reduced nsp3’s de-ADP-ribosylation activity in vitro. Next, we created recombinant severe acute respiratory syndrome coronavirus (SARS-CoV) strains with these mutations. These mutations led to virus attenuation and a modest reduction of viral loads in infected mice, despite normal replication in cell culture. Further, macrodomain mutant virus elicited an early, enhanced interferon (IFN), interferon-stimulated gene (ISG), and proinflammatory cytokine response in mice and in a human bronchial epithelial cell line. Using a coinfection assay, we found that inclusion of mutant virus in the inoculum protected mice from an otherwise lethal SARS-CoV infection without reducing virus loads, indicating that the changes in innate immune response were physiologically significant. In conclusion, we have established a novel function for the SARS-CoV macrodomain that implicates ADP-ribose in the regulation of the innate immune response and helps to demonstrate why this domain is conserved in CoVs. PMID:27965448

  4. Methylated glycans as conserved targets of animal and fungal innate defense

    PubMed Central

    Wohlschlager, Therese; Butschi, Alex; Grassi, Paola; Sutov, Grigorij; Gauss, Robert; Hauck, Dirk; Schmieder, Stefanie S.; Knobel, Martin; Titz, Alexander; Dell, Anne; Haslam, Stuart M.; Hengartner, Michael O.; Aebi, Markus; Künzler, Markus

    2014-01-01

    Effector proteins of innate immune systems recognize specific non-self epitopes. Tectonins are a family of β-propeller lectins conserved from bacteria to mammals that have been shown to bind bacterial lipopolysaccharide (LPS). We present experimental evidence that two Tectonins of fungal and animal origin have a specificity for O-methylated glycans. We show that Tectonin 2 of the mushroom Laccaria bicolor (Lb-Tec2) agglutinates Gram-negative bacteria and exerts toxicity toward the model nematode Caenorhabditis elegans, suggesting a role in fungal defense against bacteria and nematodes. Biochemical and genetic analysis of these interactions revealed that both bacterial agglutination and nematotoxicity of Lb-Tec2 depend on the recognition of methylated glycans, namely O-methylated mannose and fucose residues, as part of bacterial LPS and nematode cell-surface glycans. In addition, a C. elegans gene, termed samt-1, coding for a candidate membrane transport protein for the presumptive donor substrate of glycan methylation, S-adenosyl-methionine, from the cytoplasm to the Golgi was identified. Intriguingly, limulus lectin L6, a structurally related antibacterial protein of the Japanese horseshoe crab Tachypleus tridentatus, showed properties identical to the mushroom lectin. These results suggest that O-methylated glycans constitute a conserved target of the fungal and animal innate immune system. The broad phylogenetic distribution of O-methylated glycans increases the spectrum of potential antagonists recognized by Tectonins, rendering this conserved protein family a universal defense armor. PMID:24879441

  5. Conservation Seeds Activities Book. An Early Childhood Conservation Education Program.

    ERIC Educational Resources Information Center

    Griffin, Sherri

    This activities book is used with an early childhood conservation education program. The activities are presented in four color-coded sections, each section representing one of the four seasons. Each activity includes a statement of purpose, list of materials needed, instructional strategies, and a list of supplementary activities. In addition to…

  6. Modeling Innate Immune Response to Early Mycobacterium Infection

    PubMed Central

    Carvalho, Rafael V.; Kleijn, Jetty; Meijer, Annemarie H.

    2012-01-01

    In the study of complex patterns in biology, mathematical and computational models are emerging as important tools. In addition to experimental approaches, these modeling tools have recently been applied to address open questions regarding host-pathogen interaction dynamics, including the immune response to mycobacterial infection and tuberculous granuloma formation. We present an approach in which a computational model represents the interaction of the Mycobacterium infection with the innate immune system in zebrafish at a high level of abstraction. We use the Petri Net formalism to model the interaction between the key host elements involved in granuloma formation and infection dissemination. We define a qualitative model for the understanding and description of causal relations in this dynamic process. Complex processes involving cell-cell or cell-bacteria communication can be modeled at smaller scales and incorporated hierarchically into this main model; these are to be included in later elaborations. With the infection mechanism being defined on a higher level, lower-level processes influencing the host-pathogen interaction can be identified, modeled, and tested both quantitatively and qualitatively. This systems biology framework incorporates modeling to generate and test hypotheses, to perform virtual experiments, and to make experimentally verifiable predictions. Thereby it supports the unraveling of the mechanisms of tuberculosis infection. PMID:23365620

  7. Early developmental exposures shape trade-offs between acquired and innate immunity in humans

    PubMed Central

    Georgiev, Alexander V.; Kuzawa, Christopher W.; McDade, Thomas W.

    2016-01-01

    Background and objectives Life history theory predicts resource allocation trade-offs between competing functions and processes. We test the hypothesis that relative investment towards innate versus acquired immunity in humans is subject to such trade-offs and that three types of early developmental exposures are particularly salient in shaping adult immunophenotype: (i) pathogen exposure, (ii) nutritional resources; and (iii) extrinsic mortality cues. Methodology We quantified one aspect each of innate and acquired immune function, via C-reactive protein and Epstein–Barr virus antibodies, respectively, in a sample of 1248 men and women from the Philippines (ca. 21.5 years old). Early developmental exposures were assessed via long-term data collected prospectively since participants’ birth (1983–4). We calculated a standardized ratio to assess relative bias towards acquired versus innate immune function and examined its relationship to a suite of predictors via multiple regression. Results In partial support of our predictions, some of the measures of higher pathogen exposure, greater availability of nutritional resources, and lower extrinsic mortality cues in early life were associated with a bias toward acquired immunity in both men and women. The immune profile of women, in particular, appeared to be more sensitive to early life pathogen exposures than those of men. Finally, contrary to prediction, women exhibited a greater relative investment toward innate, not acquired, immunity. Conclusions and implications Early environments can exert considerable influence on the development of immunity. They affect trade-offs between innate and acquired immunity, which show adaptive plasticity and may differ in their influence in men and women. PMID:27530543

  8. The effects of early weaning on innate immune responses of Holstein calves

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The objectives of this study were to compare innate immune responses of calves weaned early (EW; n = 23; weaned at 23.7 ± 2.3 d of age) to conventionally-weaned calves (CW; n = 22; weaned at 44.7 ± 2.3 d of age). All calves were fed 3.8 L of colostrum within 12 h of birth and were subsequently fed m...

  9. Innate immune gene expression differentiates the early avian intestinal response between Salmonella and Campylobacter.

    PubMed

    Shaughnessy, Ronan G; Meade, Kieran G; Cahalane, Sarah; Allan, Brenda; Reiman, Carla; Callanan, John J; O'Farrelly, Cliona

    2009-12-15

    Salmonella enterica serovar Typhimurium and Campylobacter jejuni are major human pathogens, yet colonise chickens without causing pathology. The aim of this study was to compare intestinal innate immune responses to both bacterial species, in a 4-week-old broiler chicken model. Challenged and control birds were sacrificed and tissue samples taken for histopathology and RNA extraction. No significant clinical or pathological changes were observed in response to infection with either bacterial species. Expression of selected genes involved in pathogen detection and the innate immune response were profiled in caecal tissues by quantitative real-time PCR. TLR4 and TLR21 gene expression was transiently increased in response to both bacterial species (P<0.05). Significant increases in TLR5 and TLR15 gene expression were detected in response to S. Typhimurium but not to C. jejuni. Transient increases of proinflammatory cytokine (IL6 and IFNG) and chemokine (IL8 and K60) genes increased as early as 6h in response to S. Typhimurium. Minimal cytokine gene expression was detected in response to C. jejuni after 20h. IL8 gene expression however, was significantly increased by 24-fold (P<0.01). The differential expression profiles of innate immune genes in both infection models shed light on the tailored responses of the host immune system to specific microbes. It is further evidence that innate regulation of these responses is an important prerequisite to preventing development of disease.

  10. A zebrafish larval model reveals early tissue-specific innate immune responses to Mucor circinelloides.

    PubMed

    Voelz, Kerstin; Gratacap, Remi L; Wheeler, Robert T

    2015-11-01

    Mucormycosis is an emerging fungal infection that is clinically difficult to manage, with increasing incidence and extremely high mortality rates. Individuals with diabetes, suppressed immunity or traumatic injury are at increased risk of developing disease. These individuals often present with defects in phagocytic effector cell function. Research using mammalian models and phagocytic effector cell lines has attempted to decipher the importance of the innate immune system in host defence against mucormycosis. However, these model systems have not been satisfactory for direct analysis of the interaction between innate immune effector cells and infectious sporangiospores in vivo. Here, we report the first real-time in vivo analysis of the early innate immune response to mucormycete infection using a whole-animal zebrafish larval model system. We identified differential host susceptibility, dependent on the site of infection (hindbrain ventricle and swim bladder), as well as differential functions of the two major phagocyte effector cell types in response to viable and non-viable spores. Larval susceptibility to mucormycete spore infection was increased upon immunosuppressant treatment. We showed for the first time that macrophages and neutrophils were readily recruited in vivo to the site of infection in an intact host and that spore phagocytosis can be observed in real-time in vivo. While exploring innate immune effector recruitment dynamics, we discovered the formation of phagocyte clusters in response to fungal spores that potentially play a role in fungal spore dissemination. Spores failed to activate pro-inflammatory gene expression by 6 h post-infection in both infection models. After 24 h, induction of a pro-inflammatory response was observed only in hindbrain ventricle infections. Only a weak pro-inflammatory response was initiated after spore injection into the swim bladder during the same time frame. In the future, the zebrafish larva as a live whole

  11. Immune adjuvants in early life: targeting the innate immune system to overcome impaired adaptive response.

    PubMed

    de Brito, Cyro Alves; Goldoni, Adriana Letícia; Sato, Maria Notomi

    2009-09-01

    The neonatal phase is a transitory period characterized by an absence of memory cells, favoring a slow adaptive response prone to tolerance effects and the development of Th2-type responses. However, when appropriately stimulated, neonates may achieve an immune response comparable with adult counterparts. One strategy to stimulate the immunological response of neonates or children in early infancy has been to explore natural or synthetic ligands of cell receptors to stimulate innate immunity. The use of adjuvants for activating different cell receptors may be the key to enhancing neonatal adaptive immunity. This review highlights recent advances in the emerging field of molecular adjuvants of innate immune response and their implications for the development of immunotherapies, with particular focus on the neonatal period.

  12. Bcl-2 Inhibits the Innate Immune Response during Early Pathogenesis of Murine Congenital Muscular Dystrophy

    PubMed Central

    Jeudy, Sheila; Wardrop, Katherine E.; Alessi, Amy; Dominov, Janice A.

    2011-01-01

    Laminin α2 (LAMA2)-deficient congenital muscular dystrophy is a severe, early-onset disease caused by abnormal levels of laminin 211 in the basal lamina leading to muscle weakness, transient inflammation, muscle degeneration and impaired mobility. In a Lama2-deficient mouse model for this disease, animal survival is improved by muscle-specific expression of the apoptosis inhibitor Bcl-2, conferred by a MyoD-hBcl-2 transgene. Here we investigated early disease stages in this model to determine initial pathological events and effects of Bcl-2 on their progression. Using quantitative immunohistological and mRNA analyses we show that inflammation occurs very early in Lama2-deficient muscle, some aspects of which are reduced or delayed by the MyoD-hBcl-2 transgene. mRNAs for innate immune response regulators, including multiple Toll-like receptors (TLRs) and the inflammasome component NLRP3, are elevated in diseased muscle compared with age-matched controls expressing Lama2. MyoD-hBcl-2 inhibits induction of TLR4, TLR6, TLR7, TLR8 and TLR9 in Lama2-deficient muscle compared with non-transgenic controls, and leads to reduced infiltration of eosinophils, which are key death effector cells. This congenital disease model provides a new paradigm for investigating cell death mechanisms during early stages of pathogenesis, demonstrating that interactions exist between Bcl-2, a multifunctional regulator of cell survival, and the innate immune response. PMID:21850221

  13. Evolutionarily conserved recognition and innate immunity to fungal pathogens by the scavenger receptors SCARF1 and CD36

    PubMed Central

    Mylonakis, Eleftherios; Tampakakis, Emmanouil; Colvin, Richard A.; Seung, Edward; Puckett, Lindsay; Tai, Melissa F.; Stewart, Cameron R.; Pukkila-Worley, Read; Hickman, Suzanne E.; Moore, Kathryn J.; Calderwood, Stephen B.; Hacohen, Nir; Luster, Andrew D.; El Khoury, Joseph

    2009-01-01

    Receptors involved in innate immunity to fungal pathogens have not been fully elucidated. We show that the Caenorhabditis elegans receptors CED-1 and C03F11.3, and their mammalian orthologues, the scavenger receptors SCARF1 and CD36, mediate host defense against two prototypic fungal pathogens, Cryptococcus neoformans and Candida albicans. CED-1 and C03F11.1 mediated antimicrobial peptide production and were necessary for nematode survival after C. neoformans infection. SCARF1 and CD36 mediated cytokine production and were required for macrophage binding to C. neoformans, and control of the infection in mice. Binding of these pathogens to SCARF1 and CD36 was β-glucan dependent. Thus, CED-1/SCARF1 and C03F11.3/CD36 are β-glucan binding receptors and define an evolutionarily conserved pathway for the innate sensing of fungal pathogens. PMID:19237602

  14. Comparative biology of the pentraxin protein family: evolutionarily conserved component of innate immune system.

    PubMed

    Armstrong, Peter B

    2015-01-01

    The immune system is based on the actions of the collection of specialized immune defense cells and their secreted proteins and peptides that defend the host against infection by parasites. Parasites are organisms that live part or all of their lives in close physical association with the host and extract nutrients from the host and, by releasing toxins and virulence factors, cause disease with the potential for injury and premature death of that host. Parasites of the metazoa can be viruses, eubacteria, fungi, protozoans, and other metazoans. The immune system operates to kill or eliminate parasites and eliminate or detoxify their toxins and virulence factors. Although some of the elements of immune systems are specific to a particular phylum of metazoans, others show extensive evolutionary conservation, being present in several or all major phyla of the metazoa. The pentraxins display this latter character in their roles in immune defense. Pentraxins have been documented in vertebrates, nonvertebrate chordates, arthropods, and mollusks and may be present in other taxa of metazoans. Presumably the pentraxins appeared early in the evolution of metazoa, prior to their evolutionary divergence in the Precambrian epoch into many phyla present today, and have been preserved for the 542 million years since that explosive evolutionary radiation. The fidelity with which these phyla have preserved the pentraxins suggests that the functions of these proteins are important for survival of the members of these diverse taxa of animals.

  15. Toll-like receptor 7 mediates early innate immune responses to malaria.

    PubMed

    Baccarella, Alyssa; Fontana, Mary F; Chen, Eunice C; Kim, Charles C

    2013-12-01

    Innate immune recognition of malaria parasites is the critical first step in the development of the host response. At present, Toll-like receptor 9 (TLR9) is thought to play a central role in sensing malaria infection. However, we and others have observed that Tlr9(-/-) mice, in contrast to mice deficient in the downstream adaptor, Myeloid differentiation primary response gene 88 (MYD88), exhibit few deficiencies in immune function during early infection with the malaria parasite Plasmodium chabaudi, implying that another MYD88-dependent receptor also contributes to the antimalarial response. Here we use candidate-based screening to identify TLR7 as a key sensor of early P. chabaudi infection. We show that TLR7 mediates a rapid systemic response to infection through induction of cytokines such as type I interferons (IFN-I), interleukin 12, and gamma interferon. TLR7 is also required for induction of IFN-I by other species and strains of Plasmodium, including an etiological agent of human disease, P. falciparum, suggesting that malaria parasites harbor a common pathogen-associated molecular pattern (PAMP) recognized by TLR7. In contrast to the nonredundant requirement for TLR7 in early immune activation, sensing through both TLR7 and TLR9 was required for proinflammatory cytokine production and immune cell activation during the peak of parasitemia. Our findings indicate that TLR7 plays a central role in early immune activation during malaria infection, whereas TLR7 and TLR9 contribute combinatorially to immune responses as infection progresses.

  16. The involvement of cysteine-rich intestinal protein in early development and innate immunity of Asiatic hard clam, Meretrix meretrix.

    PubMed

    Chen, Hongjian; Yang, Xue; Tang, Ting; Li, Juan; Liu, Baozhong; Liu, Fengsong; Xie, Song

    2014-10-01

    Cysteine-rich intestinal protein (CRIP), a Zn(2+)-binding protein, contains a single copy of the highly conserved double-zinc-finger structure known as the LIM (lin-11-isl-1-mec-3) motif. In this paper, a cDNA encoding MmCRIP was isolated from the Asiatic hard clam Meretrix meretrix. The full-length cDNA of MmCRIP consists of a 237-bp open reading frame that encodes a polypeptide of 78 amino acids with a predicted molecular weight (MW) of 8635.8 Da and theoretical isoelectric point (pI) of 9.01. Bioinformatics analysis showed that it belonged to a new member of the CRIP subfamily. Relationship analysis revealed that MmCRIP has high-levels of sequence similarity to many CRIPs reported in other animals, particularly in invertebrates. Real-time PCR analysis showed that the highest level of MmCRIP expression was in hemocyte tissue and at pediveligers stage. To investigate immune function, mature clams were challenged with Aeromonas hydrophila. During A. hydrophila infection, up-regulation of MmCRIP transcript in clam's hemocyte, gill and hepatopancreas was detected. DsRNAi (double-strand RNA interference) approach was employed to study the function of MmCRIP and the data showed that inactivation of the MmCRIP gene blocked larvae development and caused mass mortalities. The probable roles of MmCRIP in clam early development and innate immunity are presented for the first time.

  17. Structure of human cGAS reveals a conserved family of second-messenger enzymes in innate immunity.

    PubMed

    Kranzusch, Philip J; Lee, Amy Si-Ying; Berger, James M; Doudna, Jennifer A

    2013-05-30

    Innate immune recognition of foreign nucleic acids induces protective interferon responses. Detection of cytosolic DNA triggers downstream immune signaling through activation of cyclic GMP-AMP synthase (cGAS). We report here the crystal structure of human cGAS, revealing an unanticipated zinc-ribbon DNA-binding domain appended to a core enzymatic nucleotidyltransferase scaffold. The catalytic core of cGAS is structurally homologous to the RNA-sensing enzyme, 2'-5' oligo-adenylate synthase (OAS), and divergent C-terminal domains account for specific ligand-activation requirements of each enzyme. We show that the cGAS zinc ribbon is essential for STING-dependent induction of the interferon response and that conserved amino acids displayed within the intervening loops are required for efficient cytosolic DNA recognition. These results demonstrate that cGAS and OAS define a family of innate immunity sensors and that structural divergence from a core nucleotidyltransferase enables second-messenger responses to distinct foreign nucleic acids.

  18. Myd88 Initiates Early Innate Immune Responses and Promotes CD4 T Cells during Coronavirus Encephalomyelitis

    PubMed Central

    Butchi, Niranjan; Kapil, Parul; Puntambekar, Shweta; Stohlman, Stephen A.; Hinton, David R.

    2015-01-01

    ABSTRACT Myd88 signaling is critical to the control of numerous central nervous system (CNS) infections by promoting both innate and adaptive immune responses. Nevertheless, the extent to which Myd88 regulates type I interferon (IFN) versus proinflammatory factors and T cell function, as well as the anatomical site of action, varies extensively with the pathogen. CNS infection by neurotropic coronavirus with replication confined to the brain and spinal cord induces protective IFN-α/β via Myd88-independent activation of melanoma differentiation-associated gene 5 (MDA5). However, a contribution of Myd88-dependent signals to CNS pathogenesis has not been assessed. Infected Myd88−/− mice failed to control virus, exhibited enhanced clinical disease coincident with increased demyelination, and succumbed to infection within 3 weeks. The induction of IFN-α/β, as well as of proinflammatory cytokines and chemokines, was impaired early during infection. However, defects in both IFN-α/β and select proinflammatory factors were rapidly overcome prior to T cell recruitment. Myd88 deficiency also specifically blunted myeloid and CD4 T cell recruitment into the CNS without affecting CD8 T cells. Moreover, CD4 T cells but not CD8 T cells were impaired in IFN-γ production. Ineffective virus control indeed correlated most prominently with reduced antiviral IFN-γ in the CNS of Myd88−/− mice. The results demonstrate a crucial role for Myd88 both in early induction of innate immune responses during coronavirus-induced encephalomyelitis and in specifically promoting protective CD4 T cell activation. In the absence of these responses, functional CD8 T cells are insufficient to control viral spread within the CNS, resulting in severe demyelination. IMPORTANCE During central nervous system (CNS) infections, signaling through the adaptor protein Myd88 promotes both innate and adaptive immune responses. The extent to which Myd88 regulates antiviral type I IFN, proinflammatory

  19. Heme oxygenase 1 controls early innate immune response of macrophages to Salmonella Typhimurium infection.

    PubMed

    Mitterstiller, Anna-Maria; Haschka, David; Dichtl, Stefanie; Nairz, Manfred; Demetz, Egon; Talasz, Heribert; Soares, Miguel P; Einwallner, Elisa; Esterbauer, Harald; Fang, Ferric C; Geley, Stephan; Weiss, Guenter

    2016-10-01

    Macrophages are central for the immune control of intracellular microbes. Heme oxygenase 1 (HO-1, hmox) is the first and rate limiting enzyme in the breakdown of heme originating from degraded senescent erythrocytes and heme-proteins, yielding equal amounts of iron, carbon monoxide and biliverdin. HO-1 is strongly up-regulated in macrophages in response to inflammatory signals, including bacterial endotoxin. In view of the essential role of iron for the growth and proliferation of intracellular bacteria along with known effects of the metal on innate immune function, we examined whether HO-1 plays a role in the control of infection with the intracellular bacterium Salmonella Typhimurium. We studied the course of infection in stably-transfected murine macrophages (RAW264.7) bearing a tetracycline-inducible plasmid producing hmox shRNA and in primary HO-1 knockout macrophages. While uptake of bacteria into macrophages was not affected, a significantly reduced survival of intracellular Salmonella was observed upon hmox knockdown or pharmacological hmox inhibition, which was independent of Nramp1 functionality. This could be traced to limitation of iron availability for intramacrophage bacteria along with enhanced stimulation of innate immune effector pathways, including the formation of reactive oxygen and nitrogen species and increased TNF-α expression. Mechanistically, these latter effects result from intracellular iron limitation with subsequent activation of NF-κB and further inos, tnfa and p47phox transcription along with reduced formation of the anti-inflammatory and radical scavenging molecules, CO and biliverdin as a consequence of HO-1 silencing. Taken together our data provide novel evidence that the infection-driven induction of HO-1 exerts detrimental effects in the early control of Salmonella infection, whereas hmox inhibition can favourably modulate anti-bacterial immune effector pathways of macrophages and promote bacterial elimination.

  20. Innate immunity and adjuvants

    PubMed Central

    Akira, Shizuo

    2011-01-01

    Innate immunity was for a long time considered to be non-specific because the major function of this system is to digest pathogens and present antigens to the cells involved in acquired immunity. However, recent studies have shown that innate immunity is not non-specific, but is instead sufficiently specific to discriminate self from pathogens through evolutionarily conserved receptors, designated Toll-like receptors (TLRs). Indeed, innate immunity has a crucial role in early host defence against invading pathogens. Furthermore, TLRs were found to act as adjuvant receptors that create a bridge between innate and adaptive immunity, and to have important roles in the induction of adaptive immunity. This paradigm shift is now changing our thinking on the pathogenesis and treatment of infectious, immune and allergic diseases, as well as cancers. Besides TLRs, recent findings have revealed the presence of a cytosolic detector system for invading pathogens. I will review the mechanisms of pathogen recognition by TLRs and cytoplasmic receptors, and then discuss the roles of these receptors in the development of adaptive immunity in response to viral infection. PMID:21893536

  1. Phagocytosis by Thrombocytes is a Conserved Innate Immune Mechanism in Lower Vertebrates

    PubMed Central

    Nagasawa, Takahiro; Nakayasu, Chihaya; Rieger, Aja M.; Barreda, Daniel R.; Somamoto, Tomonori; Nakao, Miki

    2014-01-01

    Thrombocytes, nucleated hemostatic blood cells of non-mammalian vertebrates, are regarded as the functional equivalent of anucleated mammalian platelets. Additional immune functions, including phagocytosis, have also been suggested for thrombocytes, but no conclusive molecular or cellular experimental evidence for their potential ingestion and clearance of infiltrating microbes has been provided till date. In the present study, we demonstrate the active phagocytic ability of thrombocytes in lower vertebrates using teleost fishes and amphibian models. Ex vivo, common carp thrombocytes were able to ingest live bacteria as well as latex beads (0.5–3 μm in diameter) and kill the bacteria. In vivo, we found that thrombocytes represented nearly half of the phagocyte population in the common carp total peripheral blood leukocyte pool. Phagocytosis efficiency was further enhanced by serum opsonization. Particle internalization led to phagolysosome fusion and killing of internalized bacteria, pointing to a robust ability for microbe elimination. We find that this potent phagocytic activity is shared across teleost (Paralichthys olivaceus) and amphibian (Xenopus laevis) models examined, implying its conservation throughout the lower vertebrate lineage. Our results provide novel insights into the dual nature of thrombocytes in the immune and homeostatic response and further provide a deeper understanding of the potential immune function of mammalian platelets based on the conserved and vestigial functions. PMID:25278940

  2. Breastmilk-Saliva Interactions Boost Innate Immunity by Regulating the Oral Microbiome in Early Infancy

    PubMed Central

    Al-Shehri, Saad S.; Knox, Christine L.; Liley, Helen G.; Cowley, David M.; Wright, John R.; Henman, Michael G.; Hewavitharana, Amitha K.; Charles, Bruce G.; Shaw, Paul N.; Sweeney, Emma L.; Duley, John A.

    2015-01-01

    Introduction Xanthine oxidase (XO) is distributed in mammals largely in the liver and small intestine, but also is highly active in milk where it generates hydrogen peroxide (H2O2). Adult human saliva is low in hypoxanthine and xanthine, the substrates of XO, and high in the lactoperoxidase substrate thiocyanate, but saliva of neonates has not been examined. Results Median concentrations of hypoxanthine and xanthine in neonatal saliva (27 and 19 μM respectively) were ten-fold higher than in adult saliva (2.1 and 1.7 μM). Fresh breastmilk contained 27.3±12.2 μM H2O2 but mixing baby saliva with breastmilk additionally generated >40 μM H2O2, sufficient to inhibit growth of the opportunistic pathogens Staphylococcus aureus and Salmonella spp. Oral peroxidase activity in neonatal saliva was variable but low (median 7 U/L, range 2–449) compared to adults (620 U/L, 48–1348), while peroxidase substrate thiocyanate in neonatal saliva was surprisingly high. Baby but not adult saliva also contained nucleosides and nucleobases that encouraged growth of the commensal bacteria Lactobacillus, but inhibited opportunistic pathogens; these nucleosides/bases may also promote growth of immature gut cells. Transition from neonatal to adult saliva pattern occurred during the weaning period. A survey of saliva from domesticated mammals revealed wide variation in nucleoside/base patterns. Discussion and Conclusion During breast-feeding, baby saliva reacts with breastmilk to produce reactive oxygen species, while simultaneously providing growth-promoting nucleotide precursors. Milk thus plays more than a simply nutritional role in mammals, interacting with infant saliva to produce a potent combination of stimulatory and inhibitory metabolites that regulate early oral–and hence gut–microbiota. Consequently, milk-saliva mixing appears to represent unique biochemical synergism which boosts early innate immunity. PMID:26325665

  3. Effects of early developmental conditions on innate immunity are only evident under favourable adult conditions in zebra finches

    NASA Astrophysics Data System (ADS)

    de Coster, Greet; Verhulst, Simon; Koetsier, Egbert; de Neve, Liesbeth; Briga, Michael; Lens, Luc

    2011-12-01

    Long-term effects of unfavourable conditions during development can be expected to depend on the quality of the environment experienced by the same individuals during adulthood. Yet, in the majority of studies, long-term effects of early developmental conditions have been assessed under favourable adult conditions only. The immune system might be particularly vulnerable to early environmental conditions as its development, maintenance and use are thought to be energetically costly. Here, we studied the interactive effects of favourable and unfavourable conditions during nestling and adult stages on innate immunity (lysis and agglutination scores) of captive male and female zebra finches ( Taeniopygia guttata). Nestling environmental conditions were manipulated by a brood size experiment, while a foraging cost treatment was imposed on the same individuals during adulthood. This combined treatment showed that innate immunity of adult zebra finches is affected by their early developmental conditions and varies between both sexes. Lysis scores, but not agglutination scores, were higher in individuals raised in small broods and in males. However, these effects were only present in birds that experienced low foraging costs. This study shows that the quality of the adult environment may shape the long-term consequences of early developmental conditions on innate immunity, as long-term effects of nestling environment were only evident under favourable adult conditions.

  4. A Conserved Circular Network of Coregulated Lipids Modulates Innate Immune Responses.

    PubMed

    Köberlin, Marielle S; Snijder, Berend; Heinz, Leonhard X; Baumann, Christoph L; Fauster, Astrid; Vladimer, Gregory I; Gavin, Anne-Claude; Superti-Furga, Giulio

    2015-07-02

    Lipid composition affects the biophysical properties of membranes that provide a platform for receptor-mediated cellular signaling. To study the regulatory role of membrane lipid composition, we combined genetic perturbations of sphingolipid metabolism with the quantification of diverse steps in Toll-like receptor (TLR) signaling and mass spectrometry-based lipidomics. Membrane lipid composition was broadly affected by these perturbations, revealing a circular network of coregulated sphingolipids and glycerophospholipids. This evolutionarily conserved network architecture simultaneously reflected membrane lipid metabolism, subcellular localization, and adaptation mechanisms. Integration of the diverse TLR-induced inflammatory phenotypes with changes in lipid abundance assigned distinct functional roles to individual lipid species organized across the network. This functional annotation accurately predicted the inflammatory response of cells derived from patients suffering from lipid storage disorders, based solely on their altered membrane lipid composition. The analytical strategy described here empowers the understanding of higher-level organization of membrane lipid function in diverse biological systems.

  5. A Conserved Circular Network of Coregulated Lipids Modulates Innate Immune Responses

    PubMed Central

    Köberlin, Marielle S.; Snijder, Berend; Heinz, Leonhard X.; Baumann, Christoph L.; Fauster, Astrid; Vladimer, Gregory I.; Gavin, Anne-Claude; Superti-Furga, Giulio

    2015-01-01

    Summary Lipid composition affects the biophysical properties of membranes that provide a platform for receptor-mediated cellular signaling. To study the regulatory role of membrane lipid composition, we combined genetic perturbations of sphingolipid metabolism with the quantification of diverse steps in Toll-like receptor (TLR) signaling and mass spectrometry-based lipidomics. Membrane lipid composition was broadly affected by these perturbations, revealing a circular network of coregulated sphingolipids and glycerophospholipids. This evolutionarily conserved network architecture simultaneously reflected membrane lipid metabolism, subcellular localization, and adaptation mechanisms. Integration of the diverse TLR-induced inflammatory phenotypes with changes in lipid abundance assigned distinct functional roles to individual lipid species organized across the network. This functional annotation accurately predicted the inflammatory response of cells derived from patients suffering from lipid storage disorders, based solely on their altered membrane lipid composition. The analytical strategy described here empowers the understanding of higher-level organization of membrane lipid function in diverse biological systems. PMID:26095250

  6. A conserved Toll-like receptor is required for Caenorhabditis elegans innate immunity

    PubMed Central

    Tenor, Jennifer L; Aballay, Alejandro

    2008-01-01

    Pathogen recognition through Toll-like receptors (TLRs) is crucial in order to mount an appropriate immune response against microorganisms. On the basis of a lack of evidence indicating that Caenorhabditis elegans uses TLRs to elicit an immune response and on the absence of genes encoding Rel-like transcription factors in its genome, it is believed that TLR-mediated immunity arose after coelomates split from pseudocoelomates and acoelomates. Here, we show that C. elegans tol-1(nr2033) mutants are killed by the human pathogen Salmonella enterica, which causes a significant pharyngeal invasion in the absence of TOL-1-mediated immunity. We also show that TOL-1 is required for the correct expression of ABF-2, which is a defensin-like molecule expressed in the pharynx, and heat-shock protein 16.41, which is also expressed in the pharynx and is part of a HSP family of proteins required for C. elegans immunity. The results indicate that TOL-1 has a direct role in defence response to certain Gram-negative bacteria and indicate that part of the TLR-mediated immunity might be evolutionarily conserved. PMID:17975555

  7. A conserved Toll-like receptor is required for Caenorhabditis elegans innate immunity.

    PubMed

    Tenor, Jennifer L; Aballay, Alejandro

    2008-01-01

    Pathogen recognition through Toll-like receptors (TLRs) is crucial in order to mount an appropriate immune response against microorganisms. On the basis of a lack of evidence indicating that Caenorhabditis elegans uses TLRs to elicit an immune response and on the absence of genes encoding Rel-like transcription factors in its genome, it is believed that TLR-mediated immunity arose after coelomates split from pseudocoelomates and acoelomates. Here, we show that C. elegans tol-1(nr2033) mutants are killed by the human pathogen Salmonella enterica, which causes a significant pharyngeal invasion in the absence of TOL-1-mediated immunity. We also show that TOL-1 is required for the correct expression of ABF-2, which is a defensin-like molecule expressed in the pharynx, and heat-shock protein 16.41, which is also expressed in the pharynx and is part of a HSP family of proteins required for C. elegans immunity. The results indicate that TOL-1 has a direct role in defence response to certain Gram-negative bacteria and indicate that part of the TLR-mediated immunity might be evolutionarily conserved.

  8. Maternal nutrient restriction during early fetal kidney development attenuates the renal innate inflammatory response in obese young adult offspring.

    PubMed

    Sharkey, Don; Gardner, David S; Symonds, Michael E; Budge, Helen

    2009-11-01

    Obesity is an independent risk factor for developing chronic kidney disease. Toll-like receptor 4 (TLR4), interleukin (IL)-18, and uncoupling protein 2 (UCP2) are important components of the innate immune system mediating inflammatory renal damage. Early to midgestation maternal nutrient restriction appears to protect the kidney from the deleterious effects of early onset obesity, although the mechanisms remain unclear. We examined the combined effects of gestational maternal nutrient restriction during early fetal kidney development and early onset obesity on the renal innate immune response in offspring. Pregnant sheep were randomly assigned to a normal (control, 100%) or nutrient-restricted (NR, 50%) diet from days 30 to 80 gestation and 100% thereafter. Offspring were killed humanely at 7 days or, following rearing in an obesogenic environment, at 1 yr of age, and renal tissues were collected. IL-18 and TLR4 expression were strongly correlated irrespective of intervention. Seven-day NR offspring had significantly lower relative renal mass and IL-18 mRNA expression. At 1 yr of age, obesity resulted in increased mRNA abundance of TLR4, IL-18, and UCP2, coupled with tubular atrophy and greater immunohistological staining of glomerular IL-6 and medullary tumor necrosis factor (TNF)-alpha. NR obese offspring had a marked reduction of TLR4 abundance and renal IL-6 staining. In conclusion, maternal nutrient restriction during early fetal kidney development attenuates the effects of early onset obesity-related nephropathy, in part, through the downregulation of the innate inflammatory response. A better understanding of maternal nutrition and the in utero nutritional environment may offer therapeutic strategies aimed at reducing the burden of later kidney disease.

  9. Widespread Shortening of 3' Untranslated Regions and Increased Exon Inclusion Are Evolutionarily Conserved Features of Innate Immune Responses to Infection.

    PubMed

    Pai, Athma A; Baharian, Golshid; Pagé Sabourin, Ariane; Brinkworth, Jessica F; Nédélec, Yohann; Foley, Joseph W; Grenier, Jean-Christophe; Siddle, Katherine J; Dumaine, Anne; Yotova, Vania; Johnson, Zachary P; Lanford, Robert E; Burge, Christopher B; Barreiro, Luis B

    2016-09-01

    The contribution of pre-mRNA processing mechanisms to the regulation of immune responses remains poorly studied despite emerging examples of their role as regulators of immune defenses. We sought to investigate the role of mRNA processing in the cellular responses of human macrophages to live bacterial infections. Here, we used mRNA sequencing to quantify gene expression and isoform abundances in primary macrophages from 60 individuals, before and after infection with Listeria monocytogenes and Salmonella typhimurium. In response to both bacteria we identified thousands of genes that significantly change isoform usage in response to infection, characterized by an overall increase in isoform diversity after infection. In response to both bacteria, we found global shifts towards (i) the inclusion of cassette exons and (ii) shorter 3' UTRs, with near-universal shifts towards usage of more upstream polyadenylation sites. Using complementary data collected in non-human primates, we show that these features are evolutionarily conserved among primates. Following infection, we identify candidate RNA processing factors whose expression is associated with individual-specific variation in isoform abundance. Finally, by profiling microRNA levels, we show that 3' UTRs with reduced abundance after infection are significantly enriched for target sites for particular miRNAs. These results suggest that the pervasive usage of shorter 3' UTRs is a mechanism for particular genes to evade repression by immune-activated miRNAs. Collectively, our results suggest that dynamic changes in RNA processing may play key roles in the regulation of innate immune responses.

  10. Inflammatory monocytes mediate early and organ-specific innate defense during systemic candidiasis.

    PubMed

    Ngo, Lisa Y; Kasahara, Shinji; Kumasaka, Debra K; Knoblaugh, Sue E; Jhingran, Anupam; Hohl, Tobias M

    2014-01-01

    Candida albicans is a commensal fungus that can cause systemic disease in patients with breaches in mucosal integrity, indwelling catheters, and defects in phagocyte function. Although circulating human and murine monocytes bind C. albicans and promote inflammation, it remains unclear whether C-C chemokine receptor 2 (CCR2)- and Ly6C-expressing inflammatory monocytes exert a protective or a deleterious function during systemic infection. During murine systemic candidiasis, interruption of CCR2-dependent inflammatory monocyte trafficking into infected kidneys impaired fungal clearance and decreased murine survival. Depletion of CCR2-expressing cells led to uncontrolled fungal growth in the kidneys and brain and demonstrated an essential antifungal role for inflammatory monocytes and their tissue-resident derivatives in the first 48 hours postinfection. Adoptive transfer of purified inflammatory monocytes in depleted hosts reversed the defect in fungal clearance to a substantial extent, indicating a compartmentally and temporally restricted protective function that can be transferred to enhance systemic innate antifungal immunity.

  11. Super-resolution microscopy reveals protein spatial reorganization in early innate immune responses.

    SciTech Connect

    Carson, Bryan D.; Aaron, Jesse S.; Timlin, Jerilyn Ann

    2010-10-01

    Over the past decade optical approaches were introduced that effectively break the diffraction barrier. Of particular note were introductions of Stimulated Emission/Depletion (STED) microscopy, Photo-Activated Localization Microscopy (PALM), and the closely related Stochastic Optical Reconstruction Microscopy (STORM). STORM represents an attractive method for researchers, as it does not require highly specialized optical setups, can be implemented using commercially available dyes, and is more easily amenable to multicolor imaging. We implemented a simultaneous dual-color, direct-STORM imaging system through the use of an objective-based TIRF microscope and filter-based image splitter. This system allows for excitation and detection of two fluorophors simultaneously, via projection of each fluorophor's signal onto separate regions of a detector. We imaged the sub-resolution organization of the TLR4 receptor, a key mediator of innate immune response, after challenge with lipopolysaccharide (LPS), a bacteria-specific antigen. While distinct forms of LPS have evolved among various bacteria, only some LPS variations (such as that derived from E. coli) typically result in significant cellular immune response. Others (such as from the plague bacteria Y. pestis) do not, despite affinity to TLR4. We will show that challenge with LPS antigens produces a statistically significant increase in TLR4 receptor clusters on the cell membrane, presumably due to recruitment of receptors to lipid rafts. These changes, however, are only detectable below the diffraction limit and are not evident using conventional imaging methods. Furthermore, we will compare the spatiotemporal behavior of TLR4 receptors in response to different LPS chemotypes in order to elucidate possible routes by which pathogens such as Y. pestis are able to circumvent the innate immune system. Finally, we will exploit the dual-color STORM capabilities to simultaneously image LPS and TLR4 receptors in the cellular

  12. Toll-like receptors in antiviral innate immunity

    PubMed Central

    Lester, Sandra N.; Li, Kui

    2014-01-01

    Toll-like receptors (TLRs) are fundamental sensor molecules of the host innate immune system, which detect conserved molecular signatures of a wide range of microbial pathogens and initiate innate immune responses via distinct signaling pathways. Various TLRs are implicated in the early interplay of host cells with invading viruses, which regulates viral replication and/or host responses, ultimately impacting on viral pathogenesis. To survive the host innate defense mechanisms, many viruses have developed strategies to evade or counteract signaling through the TLR pathways, creating an advantageous environment for their propagation. Here we review the current knowledge of the roles TLRs play in antiviral innate immune responses, discuss examples of TLR-mediated viral recognition, and describe strategies used by viruses to antagonize the host antiviral innate immune responses. PMID:24316048

  13. Adaptive immune cells temper initial innate responses

    PubMed Central

    Kim, Kwang Dong; Zhao, Jie; Auh, Sogyong; Yang, Xuanming; Du, Peishuang; Tang, Hong; Fu, Yang-Xin

    2008-01-01

    Toll-like receptors (TLRs) recognize conserved microbial structures called pathogen-associated molecular patterns. Signaling from TLRs leads to upregulation of co-stimulatory molecules for better priming of T cells and secretion of inflammatory cytokines by innate immune cells1–4. Lymphocytedeficient hosts often die of acute infection, presumably owing to their lack of an adaptive immune response to effectively clear pathogens. However, we show here that an unleashed innate immune response due to the absence of residential T cells can also be a direct cause of death. Viral infection or administration of poly(I:C), a ligand for TLR3, led to cytokine storm in T-cell- or lymphocyte-deficient mice in a fashion dependent on NK cells and tumor necrosis factor. We have further shown, through the depletion of CD4+ and CD8+ cells in wild-type mice and the transfer of T lymphocytes into Rag-1–deficient mice, respectively, that T cells are both necessary and sufficient to temper the early innate response. In addition to the effects of natural regulatory T cells, close contact of resting CD4+CD25−Foxp3− or CD8+ T cells with innate cells could also suppress the cytokine surge by various innate cells in an antigen-independent fashion. Therefore, adaptive immune cells have an unexpected role in tempering initial innate responses. PMID:17891146

  14. Adaptive immune cells temper initial innate responses.

    PubMed

    Kim, Kwang Dong; Zhao, Jie; Auh, Sogyong; Yang, Xuanming; Du, Peishuang; Tang, Hong; Fu, Yang-Xin

    2007-10-01

    Toll-like receptors (TLRs) recognize conserved microbial structures called pathogen-associated molecular patterns. Signaling from TLRs leads to upregulation of co-stimulatory molecules for better priming of T cells and secretion of inflammatory cytokines by innate immune cells. Lymphocyte-deficient hosts often die of acute infection, presumably owing to their lack of an adaptive immune response to effectively clear pathogens. However, we show here that an unleashed innate immune response due to the absence of residential T cells can also be a direct cause of death. Viral infection or administration of poly(I:C), a ligand for TLR3, led to cytokine storm in T-cell- or lymphocyte-deficient mice in a fashion dependent on NK cells and tumor necrosis factor. We have further shown, through the depletion of CD4+ and CD8+ cells in wild-type mice and the transfer of T lymphocytes into Rag-1-deficient mice, respectively, that T cells are both necessary and sufficient to temper the early innate response. In addition to the effects of natural regulatory T cells, close contact of resting CD4+CD25-Foxp3- or CD8+ T cells with innate cells could also suppress the cytokine surge by various innate cells in an antigen-independent fashion. Therefore, adaptive immune cells have an unexpected role in tempering initial innate responses.

  15. Human Immunodeficiency Virus-1 Inhibition of Immunoamphisomes in Dendritic Cells Impairs Early Innate and Adaptive Immune Responses

    PubMed Central

    Blanchet, Fabien P.; Moris, Arnaud; Nikolic, Damjan S.; Lehmann, Martin; Cardinaud, Sylvain; Stalder, Romaine; Garcia, Eduardo; Dinkins, Christina; Leuba, Florence; Wu, Li; Schwartz, Olivier; Deretic, Vojo; Piguet, Vincent

    2010-01-01

    SUMMARY Dendritic cells (DCs) in mucosal surfaces are early targets for human immunodeficiency virus-1 (HIV-1). DCs mount rapid and robust immune responses upon pathogen encounter. However, immune response in the early events of HIV-1 transmission appears limited, suggesting that HIV-1 evade early immune control by DCs. We report that HIV-1 induces a rapid shutdown of autophagy and immunoamphisomes in DCs. HIV-1 envelope activated the mammalian target of rapamycin pathway in DCs, leading to autophagy exhaustion. HIV-1-induced inhibition of autophagy in DC increased cell-associated HIV-1 and transfer of HIV-1 infection to CD4+ T cells. HIV-1-mediated downregulation of autophagy in DCs impaired innate and adaptive immune responses. Immunoamphisomes in DCs engulf incoming pathogens and appear to amplify pathogen degradation as well as Toll-like receptor responses and antigen presentation. The findings that HIV-1 downregulates autophagy and impedes immune functions of DCs represent a pathogenesis mechanism that can be pharmacologically countered with therapeutic and prophylactic implications. PMID:20451412

  16. Innate autoreactive B cells as antigen-presenting cells in the induction of tolerance to conserved keratin polypeptide.

    PubMed

    Fu, Meng; Li, Wei; Tian, Rong; Gao, Jixin; Xing, Ying; Li, Chengxin; Wang, Gang; Li, Chunying; Gao, Tianwen; Han, Hua; Liu, Yufeng

    2013-01-01

    Innate B cells account for a substantial proportion of total B lymphocytes and express autoreactive B cell receptors directed against self-constituents. However, whether innate autoreactive B cells present auto-antigens to T cells, and if so, whether they trigger an autoimmune response, are unclear. In this study, we have characterized splenic keratin-reactive B cells from naïve mice and investigated their roles in keratin antigen presentation. We observed that splenic keratin-reactive B cells expressed germline encoded VH and VK genes based on Igs from anti-keratin hybridomas. Moreover, they frequently utilized gene segment of DFL16.2 and JK2 in the CDR3 regions of heavy and light chain, suggesting that these cells are probably selected on the basis of the specificity of their BCRs. In the presence of keratin antigen, splenic keratin-reactive B cells stimulated significant IL-2 productions from keratin-specific T hybridomas, which were augmented by increasing the concentration of keratin and the numbers of keratin-reactive B cells. By contrast, keratin-reactive B cells failed to stimulate the proliferations of freshly isolated keratin-specific T cells from lymph nodes. The phenotypic analysis of splenic keratin-reactive B cells indicated that low expressions of B7-1 and B7-2 might be the underlying mechanisms for this incomplete function of B cell presentation. Our experiments indicate that splenic keratin-reactive B cells are ineffective in activating freshly isolated T cells from lymph nodes, suggesting a role for innate autoreactive B cells as antigen-presenting cells in tolerance to self-antigens.

  17. Kidney and innate immunity.

    PubMed

    Wang, Ying-Hui; Zhang, Yu-Gen

    2017-03-01

    Innate immune system is an important modulator of the inflammatory response during infection and tissue injury/repair. The kidney as a vital organ with high energy demand plays a key role in regulating the disease related metabolic process. Increasing research interest has focused on the immune pathogenesis of many kidney diseases. However, innate immune cells such as dendritic cells, macrophages, NK cells and a few innate lymphocytes, as well as the complement system are essential for renal immune homeostasis and ensure a coordinated balance between tissue injury and regeneration. The innate immune response provides the first line of host defense initiated by several classes of pattern recognition receptors (PRRs), such as membrane-bound Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), together with inflammasomes responsible for early innate immune response. Although the innate immune system is well studied, the research on the detailed relationship between innate immunity and kidney is still very limited. In this review, we will focus on the innate immune sensing system in renal immune homeostasis, as well as the corresponding pathogenesis of many kidney diseases. The pivotal roles of innate immunity in renal injury and regeneration with special emphasis on kidney disease related immunoregulatory mechanism are also discussed.

  18. Conservative constraints on early cosmology with MONTE PYTHON

    SciTech Connect

    Audren, Benjamin; Lesgourgues, Julien; Benabed, Karim; Prunet, Simon E-mail: Julien.Lesgourgues@cern.ch E-mail: prunet@iap.fr

    2013-02-01

    Models for the latest stages of the cosmological evolution rely on a less solid theoretical and observational ground than the description of earlier stages like BBN and recombination. As suggested in a previous work by Vonlanthen et al., it is possible to tweak the analysis of CMB data in such way to avoid making assumptions on the late evolution, and obtain robust constraints on ''early cosmology parameters''. We extend this method in order to marginalise the results over CMB lensing contamination, and present updated results based on recent CMB data. Our constraints on the minimal early cosmology model are weaker than in a standard ΛCDM analysis, but do not conflict with this model. Besides, we obtain conservative bounds on the effective neutrino number and neutrino mass, showing no hints for extra relativistic degrees of freedom, and proving in a robust way that neutrinos experienced their non-relativistic transition after the time of photon decoupling. This analysis is also an occasion to describe the main features of the new parameter inference code MONTE PYTHON, that we release together with this paper. MONTE PYTHON is a user-friendly alternative to other public codes like COSMOMC, interfaced with the Boltzmann code CLASS.

  19. Early local and systemic innate immune responses in the teleost gilthead seabream after intraperitoneal injection of whole yeast cells.

    PubMed

    Cuesta, Alberto; Rodríguez, Alejandro; Salinas, Irene; Meseguer, José; Esteban, M Angeles

    2007-03-01

    The early cellular innate immune responses of the teleost gilthead seabream (Sparus aurata L.) against whole yeast cells were studied. Fish received a single intraperitoneal (i.p.) injection of Saccharomyces cerevisiae and leukocyte mobilization, degranulation, peroxidase content, respiratory burst, phagocytic and cytotoxic activities were assayed in both head-kidney leukocytes (HKLs) and peritoneal exudate leukocytes (PELs). The total number of PELs significantly increased from 4 h post-injection until the end of the experiment (3 days). Interestingly, flow cytometric analysis revealed variations in the proportion of cell-types in the PE. Thus, PE acidophilic granulocytes increased to a significant extent 4 h post-injection and were restored thereafter. Moreover, PE monocyte-macrophages started to increase from 24 h, the enhancement being statistically significant after 48 and 72 h. Degranulation was greater in PELs throughout the assay. The peroxidase content of the leukocytes was affected differently in HKLs and PELs. The respiratory burst activity was not affected in HKLs but significantly increased in PELs from 4 to 48 h post-injection with yeast cells. On the other hand, HKL phagocytosis had decreased 72 h post-injection with yeast cells while it increased after 4 and 24 h post-injection in the PELs. Conversely, the cytotoxic activity was significantly enhanced in HKLs from 24 to 72 h post-injection but slightly decreased in PELs. Finally, our data demonstrate that seabream injected with the yeast Saccharomyces cerevisiae show leukocyte mobilization and cellular innate immune response activation at the site of invasion and also in the head-kidney. The implications of the leukocyte-types and the immune responses observed, as well as analogies with other particulated antigens, will be discussed as possible models for investigating the effect of potential pathogens.

  20. Early life ozone exposure results in dysregulated innate immune function and altered microRNA expression in airway epithelium.

    PubMed

    Clay, Candice C; Maniar-Hew, Kinjal; Gerriets, Joan E; Wang, Theodore T; Postlethwait, Edward M; Evans, Michael J; Fontaine, Justin H; Miller, Lisa A

    2014-01-01

    Exposure to ozone has been associated with increased incidence of respiratory morbidity in humans; however the mechanism(s) behind the enhancement of susceptibility are unclear. We have previously reported that exposure to episodic ozone during postnatal development results in an attenuated peripheral blood cytokine response to lipopolysaccharide (LPS) that persists with maturity. As the lung is closely interfaced with the external environment, we hypothesized that the conducting airway epithelium of neonates may also be a target of immunomodulation by ozone. To test this hypothesis, we evaluated primary airway epithelial cell cultures derived from juvenile rhesus macaque monkeys with a prior history of episodic postnatal ozone exposure. Innate immune function was measured by expression of the proinflammatory cytokines IL-6 and IL-8 in primary cultures established following in vivo LPS challenge or, in response to in vitro LPS treatment. Postnatal ozone exposure resulted in significantly attenuated IL-6 mRNA and protein expression in primary cultures from juvenile animals; IL-8 mRNA was also significantly reduced. The effect of antecedent ozone exposure was modulated by in vivo LPS challenge, as primary cultures exhibited enhanced cytokine expression upon secondary in vitro LPS treatment. Assessment of potential IL-6-targeting microRNAs miR-149, miR-202, and miR-410 showed differential expression in primary cultures based upon animal exposure history. Functional assays revealed that miR-149 is capable of binding to the IL-6 3' UTR and decreasing IL-6 protein synthesis in airway epithelial cell lines. Cumulatively, our findings suggest that episodic ozone during early life contributes to the molecular programming of airway epithelium, such that memory from prior exposures is retained in the form of a dysregulated IL-6 and IL-8 response to LPS; differentially expressed microRNAs such as miR-149 may play a role in the persistent modulation of the epithelial innate

  1. Early and sustained innate immune response defines pathology and death in nonhuman primates infected by highly pathogenic influenza virus

    PubMed Central

    Baskin, Carole R.; Bielefeldt-Ohmann, Helle; Tumpey, Terrence M.; Sabourin, Patrick J.; Long, James P.; García-Sastre, Adolfo; Tolnay, Airn-E.; Albrecht, Randy; Pyles, John A.; Olson, Pam H.; Aicher, Lauri D.; Rosenzweig, Elizabeth R.; Murali-Krishna, Kaja; Clark, Edward A.; Kotur, Mark S.; Fornek, Jamie L.; Proll, Sean; Palermo, Robert E.; Sabourin, Carol L.; Katze, Michael G.

    2009-01-01

    The mechanisms responsible for the virulence of the highly pathogenic avian influenza (HPAI) and of the 1918 pandemic influenza virus in humans remain poorly understood. To identify crucial components of the early host response during these infections by using both conventional and functional genomics tools, we studied 34 cynomolgus macaques (Macaca fascicularis) to compare a 2004 human H5N1 Vietnam isolate with 2 reassortant viruses possessing the 1918 hemagglutinin (HA) and neuraminidase (NA) surface proteins, known conveyors of virulence. One of the reassortants also contained the 1918 nonstructural (NS1) protein, an inhibitor of the host interferon response. Among these viruses, HPAI H5N1 was the most virulent. Within 24 h, the H5N1 virus produced severe bronchiolar and alveolar lesions. Notably, the H5N1 virus targeted type II pneumocytes throughout the 7-day infection, and induced the most dramatic and sustained expression of type I interferons and inflammatory and innate immune genes, as measured by genomic and protein assays. The H5N1 infection also resulted in prolonged margination of circulating T lymphocytes and notable apoptosis of activated dendritic cells in the lungs and draining lymph nodes early during infection. While both 1918 reassortant viruses also were highly pathogenic, the H5N1 virus was exceptional for the extent of tissue damage, cytokinemia, and interference with immune regulatory mechanisms, which may help explain the extreme virulence of HPAI viruses in humans. PMID:19218453

  2. Effect of hen age and maternal vitamin D source on performance, hatchability, bone mineral density, and progeny in vitro early innate immune function.

    PubMed

    Saunders-Blades, J L; Korver, D R

    2015-06-01

    The metabolite 25-hydroxy vitamin D3 (25-OHD) can complement or replace vitamin D3 in poultry rations, and may influence broiler production and immune function traits. The effect of broiler breeder dietary 25-OHD on egg production, hatchability, and chick early innate immune function was studied. We hypothesized that maternal dietary 25-OHD would support normal broiler breeder production and a more mature innate immune system of young chicks. Twenty-three-week-old Ross 308 hens (n=98) were placed in 4 floor pens and fed either 2,760 IU vitamin D3 (D) or 69 μg 25-OHD/kg feed. Hen weights were managed according to the primary breeder management guide. At 29 to 31 wk (Early), 46 to 48 wk (Mid), and 61 to 63 wk (Late), hens were artificially inseminated and fertile eggs incubated and hatched. Chicks were placed in cages based on maternal treatment and grown to 7 d age. Innate immune function and plasma 25-OHD were assessed at 1 and 4 d post-hatch on 15 chicks/treatment. Egg production, hen BW, and chick hatch weight were not affected by diet (P>0.05). Total in vitro Escherichia coli (E. coli) killing by 25-OHD chicks was greater than the D chicks at 4 d for the Early and Mid hatches, and 1 and 4 d for the Late hatch. This can be partly explained by the 25-OHD chicks from the Late hatch also having a greater E. coli phagocytic capability. No consistent pattern of oxidative burst response was observed. Chicks from the Mid hatch had greater percent phagocytosis, phagocytic capability, and E. coli killing than chicks from Early and Late hatches. Overall, maternal 25-OHD increased hatchability and in vitro chick innate immunity towards E. coli. Regardless of treatment, chicks from Late and Early hens had weaker early innate immune responses than chicks from Mid hens. The hen age effect tended to be the greatest factor influencing early chick innate immunity, but maternal 25-OHD also increased several measures relative to D.

  3. Polyamine transporter in Streptococcus pneumoniae is essential for evading early innate immune responses in pneumococcal pneumonia

    PubMed Central

    Rai, Aswathy N.; Thornton, Justin A.; Stokes, John; Sunesara, Imran; Swiatlo, Edwin; Nanduri, Bindu

    2016-01-01

    Streptococcus pneumoniae is the most common bacterial etiology of pneumococcal pneumonia in adults worldwide. Genomic plasticity, antibiotic resistance and extreme capsular antigenic variation complicates the design of effective therapeutic strategies. Polyamines are ubiquitous small cationic molecules necessary for full expression of pneumococcal virulence. Polyamine transport system is an attractive therapeutic target as it is highly conserved across pneumococcal serotypes. In this study, we compared an isogenic deletion strain of S. pneumoniae TIGR4 in polyamine transport operon (ΔpotABCD) with the wild type in a mouse model of pneumococcal pneumonia. Our results show that the wild type persists in mouse lung 24 h post infection while the mutant strain is cleared by host defense mechanisms. We show that intact potABCD is required for survival in the host by providing resistance to neutrophil killing. Comparative proteomics analysis of murine lungs infected with wild type and ΔpotABCD pneumococci identified expression of proteins that could confer protection to wild type strain and help establish infection. We identified ERM complex, PGLYRP1, PTPRC/CD45 and POSTN as new players in the pathogenesis of pneumococcal pneumonia. Additionally, we found that deficiency of polyamine transport leads to up regulation of the polyamine synthesis genes speE and cad in vitro. PMID:27247105

  4. Ovarian insufficiency and early pregnancy loss induced by activation of the innate immune system

    PubMed Central

    Erlebacher, Adrian; Zhang, Dorothy; Parlow, Albert F.; Glimcher, Laurie H.

    2004-01-01

    We describe a murine model of early pregnancy failure induced by systemic activation of the CD40 immune costimulatory pathway. Although fetal loss involved an NK cell intermediate, it was not due to lymphocyte-mediated destruction of the fetus and placenta. Rather, pregnancy failure resulted from impaired progesterone synthesis by the corpus luteum of the ovary, an endocrine defect in turn associated with ovarian resistance to the gonadotropic effects of prolactin. Pregnancy failure also required the proinflammatory cytokine TNF-α and correlated with the luteal induction of the prolactin receptor signaling inhibitors suppressor of cytokine signaling 1 (Socs1) and Socs3. Such links between immune activation and reproductive endocrine dysfunction may be relevant to pregnancy loss and other clinical disorders of reproduction. PMID:15232610

  5. The immune response in the CNS in Theiler's virus induced demyelinating disease switches from an early adaptive response to a chronic innate-like response.

    PubMed

    Gilli, Francesca; Li, Libin; Pachner, Andrew R

    2016-02-01

    Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) is an important model of the progressive disability caused by irreversible CNS tissue injury, and provides an example of how a CNS pathogen can cause inflammation, demyelination, and neuronal damage. We were interested in which molecules, especially inflammatory mediators, might be upregulated in the CNS throughout TMEV-IDD. We quantitated by a real-time RT-PCR multi-gene system the expression of a pathway-focused panel of genes at 30 and 165 days post infection, characterizing both the early inflammatory and the late neurodegenerative stages of TMEV-IDD. Also, we measured 32 cytokines/chemokines by multiplex Luminex analysis in CSF specimens from early and late TMEV-IDD as well as sham-treated mice. Results indicate that, in the later stage of TMEV-IDD, activation of the innate immune response is most prominent: TLRs, type I IFN response genes, and innate immunity-associated cytokines were highly expressed in late TMEV-IDD compared to sham (p ≤ 0.0001) and early TMEV-IDD (p < 0.05). Conversely, several molecular mediators of adaptive immune response were highly expressed in early TMEV-IDD (all p ≤ 0.001). Protein detection in the CSF was broadly concordant with mRNA abundance of the corresponding gene measured by real-time RT-PCR in the spinal cord, since several cytokines/chemokines were increased in the CSF of TMEV-IDD mice. Results show a clear shift from adaptive to innate immunity from early to late TMEV-IDD, indicating that adaptive and innate immune pathways are likely involved in the development and progression of the disease to different extents. CSF provides an optimal source of biomarkers of CNS neuroinflammation.

  6. Immune system development during early childhood in tropical Latin America: evidence for the age-dependent down regulation of the innate immune response.

    PubMed

    Teran, Rommy; Mitre, Edward; Vaca, Maritza; Erazo, Silvia; Oviedo, Gisela; Hübner, Marc P; Chico, Martha E; Mattapallil, Joseph J; Bickle, Quentin; Rodrigues, Laura C; Cooper, Philip J

    2011-03-01

    The immune response that develops in early childhood underlies the development of inflammatory diseases such as asthma and there are few data from tropical Latin America (LA). This study investigated the effects of age on the development of immunity during the first 5 years of life by comparing innate and adaptive immune responses in Ecuadorian children aged 6-9 months, 22-26 months, and 48-60 months. Percentages of naïve CD4+ T cells declined with age while those of memory CD4(+) and CD8(+) T cells increased indicating active development of the immune system throughout the first five years. Young infants had greater innate immune responses to TLR agonists compared to older children while regulatory responses including SEB-induced IL-10 and percentages of FoxP3(+) T-regulatory cells decreased with age. Enhanced innate immunity in early life may be important for host defense against pathogens but may increase the risk of immunopathology.

  7. Immune system development during early childhood in tropical Latin America: Evidence for the age-dependent down regulation of the innate immune response

    PubMed Central

    Teran, Rommy; Mitre, Edward; Vaca, Maritza; Erazo, Silvia; Oviedo, Gisela; Hübner, Marc P.; Chico, Martha E.; Mattapallil, Joseph J.; Bickle, Quentin; Rodrigues, Laura C.; Cooper, Philip J.

    2011-01-01

    The immune response that develops in early childhood underlies the development of inflammatory diseases such as asthma and there are few data from tropical Latin America (LA). This study investigated the effects of age on the development of immunity during the first 5 years of life by comparing innate and adaptive immune responses in Ecuadorian children aged 6–9 months, 22–26 months, and 48–60 months. Percentages of naïve CD4+ T cells declined with age while those of memory CD4+ and CD8+ T cells increased indicating active development of the immune system throughout the first five years. Young infants had greater innate immune responses to TLR agonists compared to older children while regulatory responses including SEB-induced IL-10 and percentages of FoxP3+ T-regulatory cells decreased with age. Enhanced innate immunity in early life may be important for host defense against pathogens but may increase the risk of immunopathology. PMID:21247809

  8. Widespread Shortening of 3’ Untranslated Regions and Increased Exon Inclusion Are Evolutionarily Conserved Features of Innate Immune Responses to Infection

    PubMed Central

    Pagé Sabourin, Ariane; Nédélec, Yohann; Dumaine, Anne; Yotova, Vania; Johnson, Zachary P.; Lanford, Robert E.; Burge, Christopher B.

    2016-01-01

    The contribution of pre-mRNA processing mechanisms to the regulation of immune responses remains poorly studied despite emerging examples of their role as regulators of immune defenses. We sought to investigate the role of mRNA processing in the cellular responses of human macrophages to live bacterial infections. Here, we used mRNA sequencing to quantify gene expression and isoform abundances in primary macrophages from 60 individuals, before and after infection with Listeria monocytogenes and Salmonella typhimurium. In response to both bacteria we identified thousands of genes that significantly change isoform usage in response to infection, characterized by an overall increase in isoform diversity after infection. In response to both bacteria, we found global shifts towards (i) the inclusion of cassette exons and (ii) shorter 3’ UTRs, with near-universal shifts towards usage of more upstream polyadenylation sites. Using complementary data collected in non-human primates, we show that these features are evolutionarily conserved among primates. Following infection, we identify candidate RNA processing factors whose expression is associated with individual-specific variation in isoform abundance. Finally, by profiling microRNA levels, we show that 3’ UTRs with reduced abundance after infection are significantly enriched for target sites for particular miRNAs. These results suggest that the pervasive usage of shorter 3’ UTRs is a mechanism for particular genes to evade repression by immune-activated miRNAs. Collectively, our results suggest that dynamic changes in RNA processing may play key roles in the regulation of innate immune responses. PMID:27690314

  9. Early Innate Immunity to Bacterial Infection in the Lung Is Regulated Systemically by the Commensal Microbiota via Nod-Like Receptor Ligands

    PubMed Central

    2014-01-01

    The commensal microbiota is a major regulator of the immune system. The majority of commensal bacteria inhabit the gastrointestinal tract and are known to regulate local mucosal defenses against intestinal pathogens. There is growing appreciation that the commensal microbiota also regulates immune responses at extraintestinal sites. Currently, however, it is unclear how this influences host defenses against bacterial infection outside the intestine. Microbiota depletion caused significant defects in the early innate response to lung infection by the major human pathogen Klebsiella pneumoniae. After microbiota depletion, early clearance of K. pneumoniae was impaired, and this could be rescued by administration of bacterial Nod-like receptor (NLR) ligands (the NOD1 ligand MurNAcTriDAP and NOD2 ligand muramyl dipeptide [MDP]) but not bacterial Toll-like receptor (TLR) ligands. Importantly, NLR ligands from the gastrointestinal, but not upper respiratory, tract rescued host defenses in the lung. Defects in early innate immunity were found to be due to reduced reactive oxygen species-mediated killing of bacteria by alveolar macrophages. These data show that bacterial signals from the intestine have a profound influence on establishing the levels of antibacterial defenses in distal tissues. PMID:25135683

  10. [The conservative treatment of early-stage benign prostatic hypertrophy].

    PubMed

    Kumanov, Kh; Stoianova, V; Lilov, A; Kaloianov, D

    1993-01-01

    After outlining the methods currently used in benign prostate hyperplasia (BPH) treatment, data defining some etiological aspects of the disease are briefly analyzed. Initial experience had with the treatment of early stage BPH using Permixon--a drug exerting effect on alpha-2 reductase--is described. The results in a series of twenty-seven patients presenting BPH are encouraging.

  11. Innate Immunity to Adenovirus

    PubMed Central

    Hendrickx, Rodinde; Stichling, Nicole; Koelen, Jorien; Kuryk, Lukasz; Lipiec, Agnieszka

    2014-01-01

    Abstract Human adenoviruses are the most widely used vectors in gene medicine, with applications ranging from oncolytic therapies to vaccinations, but adenovirus vectors are not without side effects. In addition, natural adenoviruses pose severe risks for immunocompromised people, yet infections are usually mild and self-limiting in immunocompetent individuals. Here we describe how adenoviruses are recognized by the host innate defense system during entry and replication in immune and nonimmune cells. Innate defense protects the host and represents a major barrier to using adenoviruses as therapeutic interventions in humans. Innate response against adenoviruses involves intrinsic factors present at constant levels, and innate factors mounted by the host cell upon viral challenge. These factors exert antiviral effects by directly binding to viruses or viral components, or shield the virus, for example, soluble factors, such as blood clotting components, the complement system, preexisting immunoglobulins, or defensins. In addition, Toll-like receptors and lectins in the plasma membrane and endosomes are intrinsic factors against adenoviruses. Important innate factors restricting adenovirus in the cytosol are tripartite motif-containing proteins, nucleotide-binding oligomerization domain-like inflammatory receptors, and DNA sensors triggering interferon, such as DEAD (Asp-Glu-Ala-Asp) box polypeptide 41 and cyclic guanosine monophosphate–adenosine monophosphate synthase. Adenovirus tunes the function of antiviral autophagy, and counters innate defense by virtue of its early proteins E1A, E1B, E3, and E4 and two virus-associated noncoding RNAs VA-I and VA-II. We conclude by discussing strategies to engineer adenovirus vectors with attenuated innate responses and enhanced delivery features. PMID:24512150

  12. Innate immune memory in plants.

    PubMed

    Reimer-Michalski, Eva-Maria; Conrath, Uwe

    2016-08-01

    The plant innate immune system comprises local and systemic immune responses. Systemic plant immunity develops after foliar infection by microbial pathogens, upon root colonization by certain microbes, or in response to physical injury. The systemic plant immune response to localized foliar infection is associated with elevated levels of pattern-recognition receptors, accumulation of dormant signaling enzymes, and alterations in chromatin state. Together, these systemic responses provide a memory to the initial infection by priming the remote leaves for enhanced defense and immunity to reinfection. The plant innate immune system thus builds immunological memory by utilizing mechanisms and components that are similar to those employed in the trained innate immune response of jawed vertebrates. Therefore, there seems to be conservation, or convergence, in the evolution of innate immune memory in plants and vertebrates.

  13. Conservation.

    ERIC Educational Resources Information Center

    National Audubon Society, New York, NY.

    This set of teaching aids consists of seven Audubon Nature Bulletins, providing the teacher and student with informational reading on various topics in conservation. The bulletins have these titles: Plants as Makers of Soil, Water Pollution Control, The Ground Water Table, Conservation--To Keep This Earth Habitable, Our Threatened Air Supply,…

  14. The Data Conservancy: Early experiences with cross-disciplinary data management

    NASA Astrophysics Data System (ADS)

    Choudhury, S.; Duerr, R. E.; Mayernik, M. S.; DiLauro, T.; Metsger, E.; Rippin, M.; Pralle, B.

    2012-12-01

    The Data Conservancy is a growing community organized around data curation research, technology development, and community building. Initially funded by the National Science Foundation's DataNet program, the Data Conservancy is headquartered at the Sheridan Libraries, Johns Hopkins University. Data Conservancy community members include university libraries, national data centers, national research labs, and information science research and education programs. The Data Conservancy Community is driven by a common theme: the need for Institutional solutions to digital research data collection, curation and preservation challenges. While firmly convinced that data curation solutions for research institutions must address both technical and organizational challenges, a significant activity within the community is the shared development of curation cyberinfrastructure. Despite many challenges, an alpha release of the Data Conservancy software (DCS) stack was publicly released at the end of August this year. While components of the DCS stack are being used by other projects, this first instantiation of the DCS is in use at two institutions, as the technical underpinnings of the Johns Hopkins University Data Management Services (JHU DMS) and at the National Snow and Ice Data Center (NSIDC) where it is being used to manage data from the Exchange for Local and Traditional Knowledge of the Arctic (ELOKA). Here we briefly provide an overview of the DCS system, describe our early experiences with the two instances of the DCS, and discuss our plans and the roadmap for the future of the Data Conservancy.

  15. Small Intestine Early Innate Immunity Response during Intestinal Colonization by Escherichia coli Depends on Its Extra-Intestinal Virulence Status

    PubMed Central

    Willing, Benjamin P.; Croxen, Matthew A.; Dufour, Nicolas; Dion, Sara; Wachtel, Sarah; Denamur, Erick; Finlay, B. Brett

    2016-01-01

    Uropathogenic Escherichia coli (UPEC) strains live as commensals in the digestive tract of the host, but they can also initiate urinary tract infections. The aim of this work was to determine how a host detects the presence of a new UPEC strain in the digestive tract. Mice were orally challenged with UPEC strains 536 and CFT073, non-pathogenic strain K12 MG1655, and ΔPAI-536, an isogenic mutant of strain 536 lacking all 7 pathogenicity islands whose virulence is drastically attenuated. Intestinal colonization was measured, and cytokine expression was determined in various organs recovered from mice after oral challenge. UPEC strain 536 efficiently colonized the mouse digestive tract, and prior Enterobacteriaceae colonization was found to impact strain 536 colonization efficiency. An innate immune response, detected as the production of TNFα, IL-6 and IL-10 cytokines, was activated in the ileum 48 hours after oral challenge with strain 536, and returned to baseline within 8 days, without a drop in fecal pathogen load. Although inflammation was detected in the ileum, histology was normal at the time of cytokine peak. Comparison of cytokine secretion 48h after oral gavage with E. coli strain 536, CFT073, MG1655 or ΔPAI-536 showed that inflammation was more pronounced with UPECs than with non-pathogenic or attenuated strains. Pathogenicity islands also seemed to be involved in host detection, as IL-6 intestinal secretion was increased after administration of E. coli strain 536, but not after administration of ΔPAI-536. In conclusion, UPEC colonization of the mouse digestive tract activates acute phase inflammatory cytokine secretion but does not trigger any pathological changes, illustrating the opportunistic nature of UPECs. This digestive tract colonization model will be useful for studying the factors controlling the switch from commensalism to pathogenicity. PMID:27096607

  16. Conservation of proteo-lipid nuclear membrane fusion machinery during early embryogenesis.

    PubMed

    Byrne, Richard D; Veeriah, Selvaraju; Applebee, Christopher J; Larijani, Banafshé

    2014-01-01

    The fusogenic lipid diacylglycerol is essential for remodeling gamete and zygote nuclear envelopes (NE) during early embryogenesis. It is unclear whether upstream signaling molecules are likewise conserved. Here we demonstrate PLCγ and its activator SFK1, which co-operate during male pronuclear envelope formation, also promote the subsequent male and female pronuclear fusion. PLCγ and SFK1 interact directly at the fusion site leading to PLCγ activation. This is accompanied by a spatially restricted reduction of PtdIns(4,5)P2. Consequently, pronuclear fusion is blocked by PLCγ or SFK1 inhibition. These findings identify new regulators of events in the early embryo and suggest a conserved "toolkit" of fusion machinery drives successive NE fusion events during embryogenesis.

  17. IFN-γ, produced by NK cells that infiltrate liver allografts early after transplantation, links the innate and adaptive immune responses1

    PubMed Central

    Obara, Hideaki; Nagasaki, Kazuhito; Hsieh, Christine L.; Ogura, Yasuhiro; Esquivel, Carlos O.; Martinez, Olivia M.; Krams, Sheri M.

    2005-01-01

    The role of NK cells following solid organ transplantation remains unclear. We examined NK cells in acute allograft rejection using a high responder model (DA → Lewis) of rat orthotopic liver transplantation. Recipient-derived NK cells infiltrated liver allografts early after transplantation. Since chemokines are important in the trafficking of cells to areas of inflammation, we determined the intragraft expression of chemokines known to attract NK cells. CCL3 was significantly increased in allografts at 6 h post-transplant as compared to syngeneic grafts whereas CCL2 and CXCL10 were elevated in both syngeneic and allogeneic grafts. CXCL10 and CX3CL1 were significantly upregulated in allografts by day three post-transplant as compared to syngeneic grafts suggesting a role for these chemokines in the recruitment of effector cells to allografts. Graft-infiltrating NK cells were shown to be a major source of IFNγ and IFNγ levels in the serum were markedly increased, specifically in allograft recipients, by day three post-transplant. Accordingly, in the absence of NK cells the levels of IFNγ were significantly decreased. Furthermore, graft survival was significantly prolonged. These data suggest that IFNγ-producing NK cells are an important link between the innate and adaptive immune responses early after transplantation. PMID:16095488

  18. Expression kinetics of key genes in the early innate immune response to Great Lakes viral hemorrhagic septicemia virus IVb infection in yellow perch (Perca flavescens)

    USGS Publications Warehouse

    Olson, Wendy; Emmenegger, Eveline; Glenn, Jolene; Simchick, Crystal; Winton, Jim; Goetz, Frederick

    2013-01-01

    The recently discovered strain of viral hemorrhagic septicemia virus, VHSV-IVb, represents an example of the introduction of an extremely pathogenic rhabdovirus capable of infecting a wide variety of new fish species in a new host-environment. The goal of the present study was to delineate the expression kinetics of key genes in the innate immune response relative to the very early stages of VHSV-IVb infection using the yellow perch (Perca flavescens) as a model. Administration of VHSV-IVb by IP-injection into juvenile yellow perch resulted in 84% cumulative mortality, indicating their high susceptibility to this disease. In fish sampled in the very early stages of infection, a significant up-regulation of Mx gene expression in the liver, as well as IL-1β and SAA activation in the head kidney, spleen, and liver was directly correlated to viral load. The potential down-regulation of Mx in the hematopoietic tissues, head kidney and spleen, may represent a strategy utilized by the virus to increase replication.

  19. Impacts of early viability selection on management of inbreeding and genetic diversity in conservation.

    PubMed

    Grueber, Catherine E; Hogg, Carolyn J; Ivy, Jamie A; Belov, Katherine

    2015-04-01

    Maintaining genetic diversity is a crucial goal of intensive management of threatened species, particularly for those populations that act as sources for translocation or re-introduction programmes. Most captive genetic management is based on pedigrees and a neutral theory of inheritance, an assumption that may be violated by selective forces operating in captivity. Here, we explore the conservation consequences of early viability selection: differential offspring survival that occurs prior to management or research observations, such as embryo deaths in utero. If early viability selection produces genotypic deviations from Mendelian predictions, it may undermine management strategies intended to minimize inbreeding and maintain genetic diversity. We use empirical examples to demonstrate that straightforward approaches, such as comparing litter sizes of inbred vs. noninbred breeding pairs, can be used to test whether early viability selection likely impacts estimates of inbreeding depression. We also show that comparing multilocus genotype data to pedigree predictions can reveal whether early viability selection drives systematic biases in genetic diversity, patterns that would not be detected using pedigree-based statistics alone. More sophisticated analysis combining genomewide molecular data with pedigree information will enable conservation scientists to test whether early viability selection drives deviations from neutrality across wide stretches of the genome, revealing whether this form of selection biases the pedigree-based statistics and inference upon which intensive management is based.

  20. Innate immunity.

    PubMed

    Revillard, Jean-Pierre

    2002-01-01

    For more than half a century immunological research has been almost exclusively orientated towards the acquired immune response and the mechanisms of immune tolerance. Major discoveries have enabled us to better understand the functioning of the specific immune system: the structure of antibody molecules, the genetic mechanisms leading to the molecular diversity of B (BCR) and T (TCR) lymphocyte antigen receptors, the biological function of major histocompatibility complex (MHC) molecules in the presentation of peptides to alpha/beta receptor bearing T lymphocytes, the processes of positive and negative selection of lymphocytes during the course of their differentiation. The major role of specific or acquired immunity has been shown by the rapidly lethal character of severe combined immune deficiency diseases and various alterations in the mechanisms of tolerance have been proposed to explain the chronic inflammatory illnesses which are considered to be auto-immune. Natural or innate immunity has been known since the first description of an inflammatory reaction attributed to Cornelius Celsus. It entered into the scientific era at the end of the 19th century with the discovery of phagocytes by Metchnikoff and of the properties of the complement system by Bordet [1] but due to the vastness of the field and its lack of clear definition, it failed to excite the interest of researchers. The discovery of cytokines and progress in knowledge of the mechanisms of the inflammatory reaction have certainly helped to banish preconceived ideas about natural immunity, which was wrongly labelled as non-specific. This has led to the proposition of a wider role for immune functions beyond the level of the cell or the organism [2] and to a better understanding of the importance of the immediate defence mechanisms and their role in the later orientation of the acquired response.

  1. Targeting Innate-Like T Cells in Tuberculosis

    PubMed Central

    Huang, Shouxiong

    2016-01-01

    Peptide-specific conventional T cells have been major targets for designing most antimycobacterial vaccines. Immune responses mediated by conventional T cells exhibit a delayed onset upon primary infection and are highly variable in different human populations. In contrast, innate-like T cells quickly respond to pathogens and display effector functions without undergoing extensive clonal expansion. Specifically, the activation of innate-like T cells depends on the promiscuous interaction of highly conserved antigen-presenting molecules, non-peptidic antigens, and likely semi-invariant T cell receptors. In antimicrobial immune responses, mucosal-associated invariant T cells are activated by riboflavin precursor metabolites presented by major histocompatibility complex-related protein I, while lipid-specific T cells including natural killer T cells are activated by lipid metabolites presented by CD1 proteins. Multiple innate-like T cell subsets have been shown to be protective or responsive in mycobacterial infections. Through rapid cytokine secretion, innate-like T cells function in early defense and memory response, offering novel advantages over conventional T cells in the design of anti-tuberculosis strategies. PMID:28066410

  2. Hydrogen, metals, bifurcating electrons, and proton gradients: the early evolution of biological energy conservation.

    PubMed

    Martin, William F

    2012-03-09

    Life is a persistent, self-specified set of far from equilibrium chemical reactions. In modern microbes, core carbon and energy metabolism are what keep cells alive. In very early chemical evolution, the forerunners of carbon and energy metabolism were the processes of generating reduced carbon compounds from CO(2) and the mechanisms of harnessing energy as compounds capable of doing some chemical work. The process of serpentinization at alkaline hydrothermal vents holds promise as a model for the origin of early reducing power, because Fe(2+) in the Earth's crust reduces water to H(2) and inorganic carbon to methane. The overall geochemical process of serpentinization is similar to the biochemical process of methanogenesis, and methanogenesis is similar to acetogenesis in that both physiologies allow energy conservation from the reduction of CO(2) with electrons from H(2). Electron bifurcation is a newly recognized cytosolic process that anaerobes use generate low potential electrons, it plays an important role in some forms of methanogenesis and, via speculation, possibly in acetogenesis. Electron bifurcation likely figures into the early evolution of biological energy conservation.

  3. Mathematical Modeling of Early Cellular Innate and Adaptive Immune Responses to Ischemia/Reperfusion Injury and Solid Organ Allotransplantation

    PubMed Central

    Day, Judy D.; Metes, Diana M.; Vodovotz, Yoram

    2015-01-01

    A mathematical model of the early inflammatory response in transplantation is formulated with ordinary differential equations. We first consider the inflammatory events associated only with the initial surgical procedure and the subsequent ischemia/reperfusion (I/R) events that cause tissue damage to the host as well as the donor graft. These events release damage-associated molecular pattern molecules (DAMPs), thereby initiating an acute inflammatory response. In simulations of this model, resolution of inflammation depends on the severity of the tissue damage caused by these events and the patient’s (co)-morbidities. We augment a portion of a previously published mathematical model of acute inflammation with the inflammatory effects of T cells in the absence of antigenic allograft mismatch (but with DAMP release proportional to the degree of graft damage prior to transplant). Finally, we include the antigenic mismatch of the graft, which leads to the stimulation of potent memory T cell responses, leading to further DAMP release from the graft and concomitant increase in allograft damage. Regulatory mechanisms are also included at the final stage. Our simulations suggest that surgical injury and I/R-induced graft damage can be well-tolerated by the recipient when each is present alone, but that their combination (along with antigenic mismatch) may lead to acute rejection, as seen clinically in a subset of patients. An emergent phenomenon from our simulations is that low-level DAMP release can tolerize the recipient to a mismatched allograft, whereas different restimulation regimens resulted in an exaggerated rejection response, in agreement with published studies. We suggest that mechanistic mathematical models might serve as an adjunct for patient- or sub-group-specific predictions, simulated clinical studies, and rational design of immunosuppression. PMID:26441988

  4. Evolutionary Conservation of the Early Axon Scaffold in the Vertebrate Brain.

    PubMed

    Ware, Michelle; Dupé, Valérie; Schubert, Frank R

    2015-10-01

    The early axon scaffold is the first axonal structure to appear in the rostral brain of vertebrates, paving the way for later, more complex connections. Several early axon scaffold components are conserved between all vertebrates; most notably two main ventral longitudinal tracts, the tract of the postoptic commissure and the medial longitudinal fascicle. While the overall structure is remarkably similar, differences both in the organization and the development of the early tracts are apparent. This review will bring together extensive data from the last 25 years in different vertebrates and for the first time, the timing and anatomy of these early tracts have been directly compared. Representatives of major vertebrate clades, including cat shark, Xenopus, chick, and mouse embryos, will be compared using immunohistochemistry staining based on previous results. There is still confusion over the nomenclature and homology of these tracts which this review will aim to address. The discussion here is relevant both for understanding the evolution of the early axon scaffold and for future studies into the molecular regulation of its formation.

  5. Early detection of tumor cells by innate immune cells leads to T(reg) recruitment through CCL22 production by tumor cells.

    PubMed

    Faget, Julien; Biota, Cathy; Bachelot, Thomas; Gobert, Michael; Treilleux, Isabelle; Goutagny, Nadège; Durand, Isabelle; Léon-Goddard, Sophie; Blay, Jean Yves; Caux, Christophe; Ménétrier-Caux, Christine

    2011-10-01

    In breast carcinomas, patient survival seems to be negatively affected by the recruitment of regulatory T cells (T(reg)) within lymphoid aggregates by CCL22. However, the mechanisms underpinning this process, which may be of broader significance in solid tumors, have yet to be described. In this study, we determined how CCL22 production is controlled in tumor cells. In human breast carcinoma cell lines, CCL22 was secreted at low basal levels that were strongly increased in response to inflammatory signals [TNF-α, IFN-γ, and interleukin (IL)-1β], contrasting with CCL17. Primary breast tumors and CD45(+) infiltrating immune cells appeared to cooperate in driving CCL22 secretion, as shown clearly in cocultures of breast tumor cell lines and peripheral blood mononuclear cells (PBMC) or their supernatants. We determined that monocyte-derived IL-1β and TNF-α are key players as monocyte depletion or neutralization of these cytokines attenuated secretion of CCL22. However, when purified monocytes were used, exogenous human IFN-γ was also required to generate this response suggesting a role for IFN-γ-producing cells within PBMCs. In this setting, we found that human IFN-γ could be replaced by the addition of (i) IL-2 or K562-activated natural killer (NK) cells or (ii) resting NK cells in the presence of anti-MHC class I antibody. Taken together, our results show a dialogue between NK and tumor cells leading to IFN-γ secretion, which in turn associates with monocyte-derived IL-1β and TNF-α to drive production of CCL22 by tumor cells and subsequent recruitment of T(reg). As one validation of this conclusion in primary breast tumors, we showed that NK cells and macrophages tend to colocalize within tumors. In summary, our findings suggest that at early times during tumorigenesis, the detection of tumor cells by innate effectors (monocytes and NK cells) imposes a selection for CCL22 secretion that recruits T(reg) to evade this early antitumor immune response.

  6. Enhanced early innate and T cell-mediated responses in subjects immunized with Anthrax Vaccine Adsorbed Plus CPG 7909 (AV7909).

    PubMed

    Minang, Jacob T; Inglefield, Jon R; Harris, Andrea M; Lathey, Janet L; Alleva, David G; Sweeney, Diane L; Hopkins, Robert J; Lacy, Michael J; Bernton, Edward W

    2014-11-28

    NuThrax™ (Anthrax Vaccine Adsorbed with CPG 7909 Adjuvant) (AV7909) is in development. Samples obtained in a phase Ib clinical trial were tested to confirm biomarkers of innate immunity and evaluate effects of CPG 7909 (PF-03512676) on adaptive immunity. Subjects received two intramuscular doses of commercial BioThrax(®) (Anthrax Vaccine Adsorbed, AVA), or two intramuscular doses of one of four formulations of AV7909. IP-10, IL-6, and C-reactive protein (CRP) levels were elevated 24-48 h after administration of AV7909 formulations, returning to baseline by Day 7. AVA (no CPG 7909) resulted in elevated IL-6 and CRP, but not IP-10. Another marker of CpG, transiently decreased absolute lymphocyte counts (ALCs), correlated with transiently increased IP-10. Cellular recall responses to anthrax protective antigen (PA) or PA peptides were assessed by IFN-γ ELISpot assay performed on cryopreserved PBMCs obtained from subjects prior to immunization and 7 days following the second immunization (study day 21). One-half of subjects that received AV7909 with low-dose (0.25mg/dose) CPG 7909 possessed positive Day 21 T cell responses to PA. In contrast, positive T cell responses occurred at an 11% average rate (1/9) for AVA-treated subjects. Differences in cellular responses due to dose level of CPG 7909 were not associated with differences in humoral anti-PA IgG responses, which were elevated for recipients of AV7909 compared to recipients of AVA. Serum markers at 24 or 48 h (i.e. % ALC decrease, or increase in IL-6, IP-10, or CRP) correlated with the humoral (antibody) responses 1 month later, but did not correlate with cellular ELISpot responses. In summary, biomarkers of early responses to CPG 7909 were confirmed, and adding a CpG adjuvant to a vaccine administered twice resulted in increased T cell effects relative to vaccine alone. Changes in early biomarkers correlated with subsequent adaptive humoral immunity but not cellular immunity.

  7. Enhanced Early Innate and T Cell-mediated Responses in Subjects Immunized with Anthrax Vaccine Adsorbed Plus CPG 7909 (AV7909)

    PubMed Central

    Minang, Jacob T.; Inglefield, Jon R.; Harris, Andrea M.; Lathey, Janet L.; Alleva, David G.; Sweeney, Diane L.; Hopkins, Robert J; Lacy, Michael J.; Bernton, Edward W.

    2014-01-01

    NuThrax™ (Anthrax Vaccine Adsorbed with CPG 7909 Adjuvant) (AV7909) is in development. Samples obtained in a Phase Ib clinical trial were tested to confirm biomarkers of innate immunity and evaluate effects of CPG 7909 (PF-03512676) on adaptive immunity. Subjects received two intramuscular doses of commercial BioThrax® (Anthrax Vaccine Adsorbed, AVA), or two intramuscular doses of one of four formulations of AV7909. IP-10, IL-6, and C-reactive protein (CRP) levels were elevated 24 to 48 hours after administration of AV7909 formulations, returning to baseline by Day 7. AVA (no CPG 7909) resulted in elevated IL-6 and CRP, but not IP-10. Another marker of CpG, transiently decreased absolute lymphocyte counts (ALC), correlated with transiently increased IP-10. Cellular recall responses to anthrax Protective Antigen (PA) or PA peptides were assessed by IFN-gamma ELISpot assay performed on cryopreserved PBMCs obtained from subjects prior to immunization and 7 days following the second immunization (study day 21). One-half of subjects that received AV7909 with low-dose (0.25 mg/dose) CPG 7909 possessed positive Day 21 T cell responses to PA. In contrast, positive T cell responses occurred at an 11% average rate (1/9) for AVA-treated subjects. Differences in cellular responses due to dose level of CPG 7909 were not associated with differences in humoral anti-PA IgG responses, which were elevated for recipients of AV7909 compared to recipients of AVA. Serum markers at 24 or 48 hours (i.e. % ALC decrease, or increase in IL-6, IP-10, or CRP) correlated with the humoral (antibody) responses 1 month later, but did not correlate with cellular ELISpot responses. In summary, biomarkers of early responses to CPG 7909 were confirmed, and adding a CpG adjuvant to a vaccine administered twice resulted in increased T cell effects relative to vaccine alone. Changes in early biomarkers correlated with subsequent adaptive humoral immunity but not cellular immunity. PMID:24530403

  8. The conserved Cockayne syndrome B-piggyBac fusion protein (CSB-PGBD3) affects DNA repair and induces both interferon-like and innate antiviral responses in CSB-null cells

    PubMed Central

    Bailey, Arnold D.; Gray, Lucas T.; Pavelitz, Thomas; Newman, John C.; Horibata, Katsuyoshi; Tanaka, Kiyoji; Weiner, Alan M.

    2012-01-01

    Cockayne syndrome is a segmental progeria most often caused by mutations in the CSB gene encoding a SWI/SNF-like ATPase required for transcription-coupled DNA repair (TCR). Over 43 Mya before marmosets diverged from humans, a piggyBac3 (PGBD3) transposable element integrated into intron 5 of the CSB gene. As a result, primate CSB genes now generate both CSB protein and a conserved CSB-PGBD3 fusion protein in which the first 5 exons of CSB are alternatively spliced to the PGBD3 transposase. Using a host cell reactivation assay, we show that the fusion protein inhibits TCR of oxidative damage but facilitates TCR of UV damage. We also show by microarray analysis that expression of the fusion protein alone in CSB-null UV-sensitive syndrome (UVSS) cells induces an interferon-like response that resembles both the innate antiviral response and the prolonged interferon response normally maintained by unphosphorylated STAT1 (U-STAT1); moreover, as might be expected based on conservation of the fusion protein, this potentially cytotoxic interferon-like response is largely reversed by coexpression of functional CSB protein. Interestingly, expression of CSB and the CSB-PGBD3 fusion protein together, but neither alone, upregulates the insulin growth factor binding protein IGFBP5 and downregulates IGFBP7, suggesting that the fusion protein may also confer a metabolic advantage, perhaps in the presence of DNA damage. Finally, we show that the fusion protein binds in vitro to members of a dispersed family of 900 internally deleted piggyBac elements known as MER85s, providing a potential mechanism by which the fusion protein could exert widespread effects on gene expression. Our data suggest that the CSB-PGBD3 fusion protein is important in both health and disease, and could play a role in Cockayne syndrome. PMID:22483866

  9. Alveolar Ridge Conservation by Early Bone Formation After Tooth Extraction in Rabbits. A Histomorphological Study.

    PubMed

    Cantín, Mario; Olate, Sergio; Fuentes, Ramón; Vásquez, Bélgica

    2015-03-01

    Alveolar ridge volume loss is an irreversible process. To prevent this physiological event, which typically result in significant local anatomical changes in both the horizontal and the vertical dimension, some strategies are indicated to minimize the loss of ridge volume that typically follows tooth extraction. The purpose of this study was to evaluate if three different bone grafts could promote new bone formation in the alveolar socket following tooth extraction for the alveolar ridge conservation. First mandibular molars of male adults rabbits were extracted and the extraction sockets were randomly treated with three different bone grafts, one xenograft and two alloplastic grafts, and a group that received no treatment (blood clot). The extraction sockets of selected rabbits from each group were evaluated at 4, 6, or 8-week post-extraction. The results indicated that the extraction sockets treated with alloplastic graft (biphasic calcium phosphate) exhibited lamellar bone formation (6.5%) as early as four weeks after the extraction was performed. Moreover, the degree of new bone formation was significantly higher (P<0.05) in the extraction sockets treated with biphasic calcium phosphate at 8-week post-extraction than that in the other study groups. In this study, we demonstrated that the proposed animal model is useful to evaluate the bone formation after tooth extraction and the alveolar ridge conservation is feasible. The new bone formation and alveolar ridge preservation with bone graft after extraction of molar teeth, could result in the maintenance of sufficient bone volume to place an implant in an ideal restorative position without the need for ancillary implant site development procedures.

  10. Alveolar Ridge Conservation by Early Bone Formation After Tooth Extraction in Rabbits. A Histomorphological Study

    PubMed Central

    Cantín, Mario; Olate, Sergio; Fuentes, Ramón; Vásquez, Bélgica

    2016-01-01

    SUMMARY Alveolar ridge volume loss is an irreversible process. To prevent this physiological event, which typically result in significant local anatomical changes in both the horizontal and the vertical dimension, some strategies are indicated to minimize the loss of ridge volume that typically follows tooth extraction. The purpose of this study was to evaluate if three different bone grafts could promote new bone formation in the alveolar socket following tooth extraction for the alveolar ridge conservation. First mandibular molars of male adults rabbits were extracted and the extraction sockets were randomly treated with three different bone grafts, one xenograft and two alloplastic grafts, and a group that received no treatment (blood clot). The extraction sockets of selected rabbits from each group were evaluated at 4, 6, or 8-week post-extraction. The results indicated that the extraction sockets treated with alloplastic graft (biphasic calcium phosphate) exhibited lamellar bone formation (6.5%) as early as four weeks after the extraction was performed. Moreover, the degree of new bone formation was significantly higher (P<0.05) in the extraction sockets treated with biphasic calcium phosphate at 8-week post-extraction than that in the other study groups. In this study, we demonstrated that the proposed animal model is useful to evaluate the bone formation after tooth extraction and the alveolar ridge conservation is feasible. The new bone formation and alveolar ridge preservation with bone graft after extraction of molar teeth, could result in the maintenance of sufficient bone volume to place an implant in an ideal restorative position without the need for ancillary implant site development procedures. PMID:27840551

  11. Chapter 2: Innate Immunity

    PubMed Central

    Turvey, Stuart E.; Broide, David H.

    2009-01-01

    Recent years have witnessed an explosion of interest in the innate immune system. Questions about how the innate immune system senses infection and empowers a protective immune response are being answered at the molecular level. These basic science discoveries are being translated into a more complete understanding of the central role innate immunity plays in the pathogenesis of many human infectious and inflammatory diseases. It is particularly exciting that we are already seeing a return on these scientific investments with the emergence of novel therapies to harness the power of the innate immune system. In this review we explore the defining characteristics of the innate immune system, and through more detailed examples, we highlight recent breakthroughs that have advanced our understanding of the role of innate immunity in human health and disease. PMID:19932920

  12. Innate Immunity in Disease

    PubMed Central

    Elliott, David E.; Siddique, Sana S.; Weinstock, Joel V.

    2014-01-01

    Cells can innately recognize generic products of viruses, bacteria, fungi, or injured tissue by engagement of pattern recognition receptors. Innate immune cells rapidly respond to this engagement in order to control commensals, thwart pathogens and/or prompt repair. Insufficient or excessive activation of the innate immune response results in disease. This review focuses on pattern recognition receptors and cells of the innate immune system important for intestinal function. Our improving knowledge pertaining to this important aspect of our immune response is opening potential important new therapeutic opportunities for the treatment of disease. PMID:24632348

  13. Evolutionarily-conserved prefrontal-amygdalar dysfunction in early-life anxiety

    PubMed Central

    Birn, Rasmus M.; Shackman, Alexander J.; Oler, Jonathan A.; Williams, Lisa E.; McFarlin, Daniel R.; Rogers, Gregory M.; Shelton, Steven E.; Alexander, Andrew L.; Pine, Daniel S.; Slattery, Marcia J.; Davidson, Richard J.; Fox, Andrew S.; Kalin, Ned H.

    2014-01-01

    Some individuals are endowed with a biology that renders them more reactive to novelty and potential threat. When extreme, this anxious temperament (AT) confers elevated risk for the development of anxiety, depression, and substance abuse. These disorders are highly prevalent, debilitating, and can be challenging to treat. The high-risk AT phenotype is expressed similarly in children and young monkeys and mechanistic work demonstrates that the central nucleus (Ce) of the amygdala is an important substrate. While it is widely believed that the flow of information across the structural network connecting the Ce to other brain regions underlies primates' capacity for flexibly regulating anxiety, the functional architecture of this network has remained poorly understood. Here we used functional magnetic resonance imaging (fMRI) in anesthetized young monkeys and quietly resting children with anxiety disorders to identify an evolutionarily-conserved pattern of functional connectivity relevant to early-life anxiety. Across primate species and levels of awareness, reduced functional connectivity between the dorsolateral prefrontal cortex (dlPFC), a region thought to play a central role in the control of cognition and emotion, and the Ce was associated with increased anxiety assessed outside the scanner. Importantly, high-resolution 18-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging provided evidence that elevated Ce metabolism statistically mediates the association between prefrontal-amygdalar connectivity and elevated anxiety. These results provide new clues about the brain network underlying extreme early-life anxiety and set the stage for mechanistic work aimed at developing improved interventions for pediatric anxiety. PMID:24863147

  14. Biopsy Findings After Breast Conservation Therapy for Early-Stage Invasive Breast Cancer

    SciTech Connect

    Vapiwala, Neha Starzyk, Jill; Harris, Eleanor E.; Tchou, Julia C.; Boraas, Marcia C.; Czerniecki, Brian J.; Rosato, Ernest F.; Orel, Susan G.; Solin, Lawrence J.

    2007-10-01

    Purpose: To determine the patterns and factors predictive of positive ipsilateral breast biopsy after conservation therapy for early-stage breast cancer. Methods and Materials: We performed a retrospective review of Stage I-II breast cancer patients initially treated with lumpectomy and radiotherapy between 1977 and 1996, who later underwent post-treatment ipsilateral breast biopsies. Results: A total of 223 biopsies were performed in 193 treated breasts: 171 single and 22 multiple biopsies. Of the 223 biopsies, 56% were positive and 44% were negative for recurrence. The positive biopsy rate (PBR) was 59% for the first and 32% for subsequent biopsies. The median time to the first post-treatment biopsy was 49 months. Of the patients with negative initial biopsy findings, 11% later developed local recurrence. The PBR was 40% among patients with physical examination findings only, 65% with mammographic abnormalities only, and 79% with both findings (p = 0.001). Analysis of the procedure type revealed a PBR of 86% for core and 58% for excisional biopsies compared with 28% for aspiration cytology alone (p = 0.025). The PBR varied inversely with age at the original diagnosis: 49% if {>=}51 years, 57% if 36-50 years, and 83% if {<=}35 years (p = 0.05). The PBR correlated directly with the interval after radiotherapy: 49% if {<=}60 months, 59% if 60.1-120 months, 77% if 120.1-180 months, and 100% if >180 months after completing postlumpectomy radiotherapy (p = 0.01). The PBR was not linked with recurrence location, initial pathologic T or N stage, estrogen receptor/progesterone receptor status, or final pathologic margins (all p {>=} 0.15). Conclusion: After definitive radiotherapy for early-stage breast cancer, a greater PBR was associated with the presence of both mammographic and clinical abnormalities, excisional or core biopsies, younger age at the initial diagnosis, and longer intervals after radiotherapy completion.

  15. Perioperative interstitial irradiation in the conservative management of early breast cancer

    SciTech Connect

    Krishnan, L.; Jewell, W.R.; Mansfield, C.M.; Reddy, E.K.; Thomas, J.H.; Krishnan, E.C.

    1987-11-01

    Conservation of the breast in early breast cancer with limited resection and radiation is proving to be as effective as modified radical mastectomy in survival and in loco-regional control. Management at the University of Kansas Medical Center consists of an interstitial implant at the time of lumpectomy to facilitate perioperative irradiation with Iridium-192 to the tumor bed. An axillary node dissection is also performed at that time. Two to 3 weeks later external beam irradiation is delivered to the entire breast. One hundred and twenty-three breasts in 120 patients have been treated between June 1982 and June 1986. There were 49 pathological Stage I, 63 Stage II, 8 Stage III carcinomas, and 3 carcinomas in situ, consisting of 72 T1, 43 T2, 5 T3, and 3 TIS lesions. Patients have been followed for a median of 30 months. One patient had a ''true'' recurrence in the breast. Another patient developed recurrence in a different quadrant. Ninety percent of the patients had good to excellent cosmetic results, 7% were considered fair, and 3% had poor results. Seven patients developed mild arm edema, 4 were found to have moderate edema, and 1 had severe arm edema. Our preliminary results indicate that interstitial irradiation immediately after excision results in excellent local control, with very satisfactory cosmesis and no morbidity due to the simultaneous excision and irradiation.

  16. True Local Recurrences after Breast Conserving Surgery have Poor Prognosis in Patients with Early Breast Cancer

    PubMed Central

    Sarsenov, Dauren; Ilgun, Serkan; Ordu, Cetin; Alco, Gul; Bozdogan, Atilla; Elbuken, Filiz; Nur Pilanci, Kezban; Agacayak, Filiz; Erdogan, Zeynep; Eralp, Yesim; Dincer, Maktav

    2016-01-01

    Background: This study was aimed at investigating clinical and histopathologic features of ipsilateral breast tumor recurrences (IBTR) and their effects on survival after breast conservation therapy. Methods: 1,400 patients who were treated between 1998 and 2007 and had breast-conserving surgery (BCS) for early breast cancer (cT1-2/N0-1/M0) were evaluated. Demographic and pathologic parameters, radiologic data, treatment, and follow-up related features of the patients were recorded. Results: 53 patients (3.8%) had IBTR after BCS within a median follow-up of 70 months. The mean age was 45.7 years (range, 27-87 years), and 22 patients (41.5%) were younger than 40 years. 33 patients (62.3%) had true recurrence (TR) and 20 were classified as new primary (NP). The median time to recurrence was shorter in TR group than in NP group (37.0 (6-216) and 47.5 (11-192) months respectively; p = 0.338). Progesterone receptor positivity was significantly higher in the NP group (p = 0.005). The overall 5-year survival rate in the NP group (95.0%) was significantly higher than that of the TR group (74.7%, p < 0.033). Multivariate analysis showed that younger age (<40 years), large tumor size (>20 mm), high grade tumor and triple-negative molecular phenotype along with developing TR negatively affected overall survival (hazard ratios were 4.2 (CI 0.98-22.76), 4.6 (CI 1.07-13.03), 4.0 (CI 0.68-46.10), 6.5 (CI 0.03-0.68), and 6.5 (CI 0.02- 0.80) respectively, p < 0.05). Conclusions: Most of the local recurrences after BCS in our study were true recurrences, which resulted in a poorer outcome as compared to new primary tumors. Moreover, younger age (<40), large tumor size (>2 cm), high grade, triple negative phenotype, and having true recurrence were identified as independent prognostic factors with a negative impact on overall survival in this dataset of patients with recurrent breast cancer. In conjunction with a more intensive follow-up program, the role of adjuvant therapy

  17. Zika Virus Infects Early- and Midgestation Human Maternal Decidual Tissues, Inducing Distinct Innate Tissue Responses in the Maternal-Fetal Interface.

    PubMed

    Weisblum, Yiska; Oiknine-Djian, Esther; Vorontsov, Olesya M; Haimov-Kochman, Ronit; Zakay-Rones, Zichria; Meir, Karen; Shveiky, David; Elgavish, Sharona; Nevo, Yuval; Roseman, Moshe; Bronstein, Michal; Stockheim, David; From, Ido; Eisenberg, Iris; Lewkowicz, Aya A; Yagel, Simcha; Panet, Amos; Wolf, Dana G

    2017-02-15

    Zika virus (ZIKV) has emerged as a cause of congenital brain anomalies and a range of placenta-related abnormalities, highlighting the need to unveil the modes of maternal-fetal transmission. The most likely route of vertical ZIKV transmission is via the placenta. The earliest events of ZIKV transmission in the maternal decidua, representing the maternal uterine aspect of the chimeric placenta, have remained unexplored. Here, we show that ZIKV replicates in first-trimester human maternal-decidual tissues grown ex vivo as three-dimensional (3D) organ cultures. An efficient viral spread in the decidual tissues was demonstrated by the rapid upsurge and continued increase of tissue-associated ZIKV load and titers of infectious cell-free virus progeny, released from the infected tissues. Notably, maternal decidual tissues obtained at midgestation remained similarly susceptible to ZIKV, whereas fetus-derived chorionic villi demonstrated reduced ZIKV replication with increasing gestational age. A genome-wide transcriptome analysis revealed that ZIKV substantially upregulated the decidual tissue innate immune responses. Further comparison of the innate tissue response patterns following parallel infections with ZIKV and human cytomegalovirus (HCMV) revealed that unlike HCMV, ZIKV did not induce immune cell activation or trafficking responses in the maternal-fetal interface but rather upregulated placental apoptosis and cell death molecular functions. The data identify the maternal uterine aspect of the human placenta as a likely site of ZIKV transmission to the fetus and further reveal distinct patterns of innate tissue responses to ZIKV. Our unique experimental model and findings could further serve to study the initial stages of congenital ZIKV transmission and pathogenesis and evaluate the effect of new therapeutic interventions.

  18. Outcomes in Black Patients With Early Breast Cancer Treated With Breast Conservation Therapy

    SciTech Connect

    Nichols, Michael A.; Mell, Loren K.; Hasselle, Michael D.; Karrison, Theodore G.; MacDermed, Dhara; Meriwether, Amber; Witt, Mary Ellyn; Weichselbaum, Ralph R.; Chmura, Steven J.

    2011-02-01

    Background: The race-specific impact of prognostic variables for early breast cancer is unknown for black patients undergoing breast conservation. Methods and Materials: This was a retrospective study of 1,231 consecutive patients {>=}40 years of age with Stage I-II invasive breast cancer treated with lumpectomy and radiation therapy at the University of Chicago Hospitals and affiliates between 1986 and 2004. Patients were classified as either black or nonblack. Cox proportional hazards regression was used to model the effects of known prognostic factors and interactions with race. Results: Median follow-up for surviving patients was 82 months. Thirty-four percent of patients were black, and 66% were nonblack (Caucasian, Hispanic, and Asian). Black patients had a poorer 10-year overall survival (64.6% vs. 80.8%; adjusted hazard ratio [HR], 1.59; 95% confidence interval [CI], 1.23-2.06) and 10-year disease-free survival (58.1% vs. 75.4%; HR 1.49; 95% CI, 1.18-1.89) compared with nonblack patients. Tumor sizes were similar between nonblack and black patients with mammographically detected tumors (1.29 cm vs. 1.20 cm, p = 0.20, respectively). Tumor size was significantly associated with overall survival (HR 1.48; 95% CI, 1.12-1.96) in black patients with mammographically detected tumors but not in nonblack patients (HR 1.09; 95% CI, 0.78-1.53), suggesting that survival in black patients depends more strongly on tumor size in this subgroup. Tests for race-size method of detection interactions were statistically significant for overall survival (p = 0.049), locoregional control (p = 0.036), and distant control (p = 0.032) and borderline significant for disease-free survival (p = 0.067). Conclusion: Despite detection at comparable sizes, the prognostic effect of tumor size in patients with mammographically detected tumors is greater for black than in nonblack patients.

  19. Prognosis for Mammographically Occult, Early-Stage Breast Cancer Patients Treated With Breast-Conservation Therapy

    SciTech Connect

    Yang, Tzu-I. J.; Yang Qifeng; Haffty, Bruce G.; Moran, Meena S.

    2010-01-15

    Purpose: To compare mammographically occult (MamOcc) and mammographically positive (MamPos) early-stage breast cancer patients treated with breast-conservation therapy (BCT), to analyze differences between the two cohorts. Methods and Materials: Our two cohorts consisted of 214 MamOcc and 2168 MamPos patients treated with BCT. Chart reviews were conducted to assess mammogram reports and method of detection. All clinical-pathologic and outcome parameters were analyzed to detect differences between the two cohorts. Results: Median follow-up was 7 years. There were no differences in final margins, T stage, nodal status, estrogen/progesterone receptor status, or 'triple-negative' status. Significant differences included younger age at diagnosis (p < 0.0001), more positive family history (p = 0.0033), less HER-2+ disease (p = 0.0294), and 1{sup o} histology (p < 0.0001). At 10 years, the differences in overall survival, cause-specific survival, and distant relapse between the two groups did not differ significantly. The MamOcc cohort had more breast relapses (15% vs. 8%; p = 0.0357), but on multivariate analysis this difference was not significant (hazard ratio 1.0, 95% confidence interval 0.993-1.007, p = 0.9296). Breast relapses were mammographically occult in 32% of the MamOcc and 12% of the MamPos cohorts (p = 0.0136). Conclusions: Although our study suggests that there are clinical-pathologic variations for the MamOcc cohort vs. MamPos patients that may ultimately affect management, breast relapse after BCT was not significantly different. Breast recurrences were more often mammographically occult in the MamOcc cohort; consideration should be given to closer follow-up and alternative imaging strategies (ultrasound, breast MRI) for routine posttreatment examination. To our knowledge, this represents the largest series addressing the prognostic significance of MamOcc cancers treated with BCT.

  20. Nucleotide sequence of a cluster of early and late genes in a conserved segment of the vaccinia virus genome.

    PubMed Central

    Plucienniczak, A; Schroeder, E; Zettlmeissl, G; Streeck, R E

    1985-01-01

    The nucleotide sequence of a 7.6 kb vaccinia DNA segment from a genomic region conserved among different orthopox virus has been determined. This segment contains a tight cluster of 12 partly overlapping open reading frames most of which can be correlated with previously identified early and late proteins and mRNAs. Regulatory signals used by vaccinia virus have been studied. Presumptive promoter regions are rich in A, T and carry the consensus sequences TATA and AATAA spaced at 20-24 base pairs. Tandem repeats of a CTATTC consensus sequence are proposed to be involved in the termination of early transcription. PMID:2987815

  1. Approaching archetypes: reconsidering innateness.

    PubMed

    Goodwyn, Erik

    2010-09-01

    The question of innateness has hounded Jungian psychology since Jung originally postulated the archetype as an a priori structure within the psyche. During his life and after his death he was continually accused of Lamarckianism and criticized for his theory that the archetypes existed as prior structures. More recently, with the advent of genetic research and the human genome project, the idea that psychological structures can be innate has come under even harsher criticism even within Jungian thought. There appears to be a growing consensus that Jung's idea of innate psychological structures was misguided, and that perhaps the archetype-as-such should be abandoned for more developmental and 'emergent' theories of the psyche. The purpose of this essay is to question this conclusion, and introduce some literature on psychological innateness that appears relevant to this discussion.

  2. Arguing about innateness.

    PubMed

    Valian, Virginia

    2014-07-01

    This paper lays out the components of a language acquisition model, the interconnections among the components, and the differing stances of nativism and empiricism about syntax. After demonstrating that parsimony cannot decide between the two stances, the paper analyzes nine examples of evidence that have been used to argue for or against nativism, concluding that most pieces of evidence are either irrelevant or suggest that language is special but need not invoke innate ideas. Two pieces of evidence - the development of home sign languages and the acquisition of Determiners - do show not just that language is special but that the child has innate syntactic content. The existential claim that nativism makes - there is at least one innate syntactic idea - is an easier claim to verify than the universal claim that empiricism makes - there are no innate syntactic ideas.

  3. Diverse Early Life-History Strategies in Migratory Amazonian Catfish: Implications for Conservation and Management.

    PubMed

    Hegg, Jens C; Giarrizzo, Tommaso; Kennedy, Brian P

    2015-01-01

    Animal migrations provide important ecological functions and can allow for increased biodiversity through habitat and niche diversification. However, aquatic migrations in general, and those of the world's largest fish in particular, are imperiled worldwide and are often poorly understood. Several species of large Amazonian catfish carry out some of the longest freshwater fish migrations in the world, travelling from the Amazon River estuary to the Andes foothills. These species are important apex predators in the main stem rivers of the Amazon Basin and make up the region's largest fishery. They are also the only species to utilize the entire Amazon Basin to complete their life cycle. Studies indicate both that the fisheries may be declining due to overfishing, and that the proposed and completed dams in their upstream range threaten spawning migrations. Despite this, surprisingly little is known about the details of these species' migrations, or their life history. Otolith microchemistry has been an effective method for quantifying and reconstructing fish migrations worldwide across multiple spatial scales and may provide a powerful tool to understand the movements of Amazonian migratory catfish. Our objective was to describe the migratory behaviors of the three most populous and commercially important migratory catfish species, Dourada (Brachyplatystoma rousseauxii), Piramutaba (Brachyplatystoma vaillantii), and Piraíba (Brachyplatystoma filamentosum). We collected fish from the mouth of the Amazon River and the Central Amazon and used strontium isotope signatures ((87)Sr/(86)Sr) recorded in their otoliths to determine the location of early rearing and subsequent. Fish location was determined through discriminant function classification, using water chemistry data from the literature as a training set. Where water chemistry data was unavailable, we successfully in predicted (87)Sr/(86)Sr isotope values using a regression-based approach that related the geology

  4. Diverse Early Life-History Strategies in Migratory Amazonian Catfish: Implications for Conservation and Management

    PubMed Central

    Hegg, Jens C.; Giarrizzo, Tommaso; Kennedy, Brian P.

    2015-01-01

    Animal migrations provide important ecological functions and can allow for increased biodiversity through habitat and niche diversification. However, aquatic migrations in general, and those of the world’s largest fish in particular, are imperiled worldwide and are often poorly understood. Several species of large Amazonian catfish carry out some of the longest freshwater fish migrations in the world, travelling from the Amazon River estuary to the Andes foothills. These species are important apex predators in the main stem rivers of the Amazon Basin and make up the region’s largest fishery. They are also the only species to utilize the entire Amazon Basin to complete their life cycle. Studies indicate both that the fisheries may be declining due to overfishing, and that the proposed and completed dams in their upstream range threaten spawning migrations. Despite this, surprisingly little is known about the details of these species’ migrations, or their life history. Otolith microchemistry has been an effective method for quantifying and reconstructing fish migrations worldwide across multiple spatial scales and may provide a powerful tool to understand the movements of Amazonian migratory catfish. Our objective was to describe the migratory behaviors of the three most populous and commercially important migratory catfish species, Dourada (Brachyplatystoma rousseauxii), Piramutaba (Brachyplatystoma vaillantii), and Piraíba (Brachyplatystoma filamentosum). We collected fish from the mouth of the Amazon River and the Central Amazon and used strontium isotope signatures (87Sr/86Sr) recorded in their otoliths to determine the location of early rearing and subsequent. Fish location was determined through discriminant function classification, using water chemistry data from the literature as a training set. Where water chemistry data was unavailable, we successfully in predicted 87Sr/86Sr isotope values using a regression-based approach that related the geology of

  5. Early Surgery versus Initial Conservative Treatment in Patients with Traumatic Intracerebral Hemorrhage (STITCH[Trauma]): The First Randomized Trial.

    PubMed

    Mendelow, A David; Gregson, Barbara A; Rowan, Elise N; Francis, Richard; McColl, Elaine; McNamee, Paul; Chambers, Iain R; Unterberg, Andreas; Boyers, Dwayne; Mitchell, Patrick M

    2015-09-01

    Intraparenchymal hemorrhages occur in a proportion of severe traumatic brain injury TBI patients, but the role of surgery in their treatment is unclear. This international multi-center, patient-randomized, parallel-group trial compared early surgery (hematoma evacuation within 12 h of randomization) with initial conservative treatment (subsequent evacuation allowed if deemed necessary). Patients were randomized using an independent randomization service within 48 h of TBI. Patients were eligible if they had no more than two intraparenchymal hemorrhages of 10 mL or more and did not have an extradural or subdural hematoma that required surgery. The primary outcome measure was the traditional dichotomous split of the Glasgow Outcome Scale obtained by postal questionnaires sent directly to patients at 6 months. The trial was halted early by the UK funding agency (NIHR HTA) for failure to recruit sufficient patients from the UK (trial registration: ISRCTN19321911). A total of 170 patients were randomized from 31 of 59 registered centers worldwide. Of 82 patients randomized to early surgery with complete follow-up, 30 (37%) had an unfavorable outcome. Of 85 patients randomized to initial conservative treatment with complete follow-up, 40 (47%) had an unfavorable outcome (odds ratio, 0.65; 95% confidence interval, CI 0.35, 1.21; p=0.17), with an absolute benefit of 10.5% (CI, -4.4-25.3%). There were significantly more deaths in the first 6 months in the initial conservative treatment group (33% vs. 15%; p=0.006). The 10.5% absolute benefit with early surgery was consistent with the initial power calculation. However, with the low sample size resulting from the premature termination, we cannot exclude the possibility that this could be a chance finding. A further trial is required urgently to assess whether this encouraging signal can be confirmed.

  6. Early Surgery versus Initial Conservative Treatment in Patients with Traumatic Intracerebral Hemorrhage (STITCH[Trauma]): The First Randomized Trial

    PubMed Central

    Mendelow, A. David; Rowan, Elise N.; Francis, Richard; McColl, Elaine; McNamee, Paul; Chambers, Iain R.; Unterberg, Andreas; Boyers, Dwayne; Mitchell, Patrick M.

    2015-01-01

    Abstract Intraparenchymal hemorrhages occur in a proportion of severe traumatic brain injury TBI patients, but the role of surgery in their treatment is unclear. This international multi-center, patient-randomized, parallel-group trial compared early surgery (hematoma evacuation within 12 h of randomization) with initial conservative treatment (subsequent evacuation allowed if deemed necessary). Patients were randomized using an independent randomization service within 48 h of TBI. Patients were eligible if they had no more than two intraparenchymal hemorrhages of 10 mL or more and did not have an extradural or subdural hematoma that required surgery. The primary outcome measure was the traditional dichotomous split of the Glasgow Outcome Scale obtained by postal questionnaires sent directly to patients at 6 months. The trial was halted early by the UK funding agency (NIHR HTA) for failure to recruit sufficient patients from the UK (trial registration: ISRCTN19321911). A total of 170 patients were randomized from 31 of 59 registered centers worldwide. Of 82 patients randomized to early surgery with complete follow-up, 30 (37%) had an unfavorable outcome. Of 85 patients randomized to initial conservative treatment with complete follow-up, 40 (47%) had an unfavorable outcome (odds ratio, 0.65; 95% confidence interval, CI 0.35, 1.21; p=0.17), with an absolute benefit of 10.5% (CI, −4.4–25.3%). There were significantly more deaths in the first 6 months in the initial conservative treatment group (33% vs. 15%; p=0.006). The 10.5% absolute benefit with early surgery was consistent with the initial power calculation. However, with the low sample size resulting from the premature termination, we cannot exclude the possibility that this could be a chance finding. A further trial is required urgently to assess whether this encouraging signal can be confirmed. PMID:25738794

  7. Innate Immune Pattern Recognition: A Cell Biological Perspective

    PubMed Central

    Brubaker, Sky W.; Bonham, Kevin S.; Zanoni, Ivan

    2016-01-01

    Receptors of the innate immune system detect conserved determinants of microbial and viral origin. Activation of these receptors initiates signaling events that culminate in an effective immune response. Recently, the view that innate immune signaling events rely on and operate within a complex cellular infrastructure has become an important framework for understanding the regulation of innate immunity. Compartmentalization within this infrastructure provides the cell with the ability to assign spatial information to microbial detection and regulate immune responses. Several cell biological processes play a role in the regulation of innate signaling responses; at the same time, innate signaling can engage cellular processes as a form of defense or to promote immunological memory. In this review, we highlight these aspects of cell biology in pattern-recognition receptor signaling by focusing on signals that originate from the cell surface, from endosomal compartments, and from within the cytosol. PMID:25581309

  8. The expression pattern of genes involved in early neurogenesis suggests distinct and conserved functions in the diplopod Glomeris marginata.

    PubMed

    Pioro, Hilary L; Stollewerk, Angelika

    2006-01-01

    We have shown recently that the expression and function of proneural genes is conserved in chelicerates and myriapods, although groups of neural precursors are specified in the ventral neuroectoderm of these arthropod groups, rather than single cells as in insects and crustaceans. We present additional evidence that the pattern of neurogenesis seen in chelicerates and in previously analyzed myriapod species is representative of both arthropod groups, by analysing the formation of neural precursors in the diplopod Archispirostreptus sp. This raises the question as to what extent the genetic network has been modified to result in different modes of neurogenesis in the arthropod group. To find out which components of the neural genetic network might account for the different mode of neural precursor formation in chelicerates and myriapods, we identified genes in the diplopod Glomeris marginata that are known to be involved in early neurogenesis in Drosophila and studied their expression pattern. In Drosophila, early neurogenesis is controlled by proneural genes that encode HLH transcription factors. These genes belong to two major subfamilies, the achaete-scute group and the atonal group. Different proneural proteins activate both a common neural programme and distinct neuronal subtype-specific target genes. We show that the expression pattern of homologs of the Drosophila proneural genes daughterless, atonal, and Sox B1 are partially conserved in Glomeris mariginata. While the expression of the pan-neural gene snail is conserved in the ventral neuroectoderm of G. marginata, we found an additional expression domain in the ventral midline. We conclude that, although the components of the genetic network involved in specification of neural precursors seem to be conserved in chelicerates, myriapods, and Drosophila, the function of some of the genes might have changed during evolution.

  9. Innate Memory T cells

    PubMed Central

    Jameson, Stephen C.; Lee, You Jeong; Hogquist, Kristin A.

    2015-01-01

    Memory T cells are usually considered to be a feature of a successful immune response against a foreign antigen, and such cells can mediate potent immunity. However, in mice, alternative pathways have been described, through which naïve T cells can acquire the characteristics and functions of memory T cells without encountering specific foreign antigen or the typical signals required for conventional T cell differentiation. Such cells reflect a response to the internal rather the external environment, and hence such cells are called innate memory T cells. In this review, we describe how innate memory subsets were identified, the signals that induce their generation and their functional properties and potential role in the normal immune response. The existence of innate memory T cells in mice raises questions about whether parallel populations exist in humans, and we discuss the evidence for such populations during human T cell development and differentiation. PMID:25727290

  10. Innate immune system cells in atherosclerosis.

    PubMed

    Chávez-Sánchez, Luis; Espinosa-Luna, Jose E; Chávez-Rueda, Karina; Legorreta-Haquet, María V; Montoya-Díaz, Eduardo; Blanco-Favela, Francisco

    2014-01-01

    Atherosclerosis is a chronic inflammatory disease of the arterial wall characterized by innate and adaptive immune system involvement. A key component of atherosclerotic plaque inflammation is the persistence of different innate immune cell types including mast cells, neutrophils, natural killer cells, monocytes, macrophages and dendritic cells. Several endogenous signals such as oxidized low-density lipoproteins, and exogenous signals such as lipopolysaccharides, trigger the activation of these cells. In particular, these signals orchestrate the early and late inflammatory responses through the secretion of pro-inflammatory cytokines and contribute to plaque evolution through the formation of foam cells, among other events. In this review we discuss how innate immune system cells affect atherosclerosis pathogenesis.

  11. Time Course of Mild Arm Lymphedema After Breast Conservation Treatment for Early-Stage Breast Cancer

    SciTech Connect

    Bar Ad, Voichita; Cheville, Andrea; Solin, Lawrence J.; Dutta, Pinaki; Both, Stefan; Harris, Eleanor

    2010-01-15

    Purpose: Arm lymphedema is a potential consequence of the treatment for breast carcinoma. The objective of this retrospective study was to characterize the progression of mild arm lymphedema after breast conservation treatment for breast cancer. Methods and Materials: The study cohort was drawn from 1,713 consecutive Stage I or II breast cancer patients who underwent breast conservation therapy, including axillary staging followed by radiation. Arm lymphedema was documented in 266 (16%) of 1,713 patients. One hundred nine patients, 6% of the overall group and 40% of the patients with arm lymphedema, presented with mild arm lymphedema, defined as a difference of 2 cm or less between the measured circumferences of the affected and unaffected arms. Results: Among the 109 patients with mild arm lymphedema at the time of arm lymphedema diagnosis, the rate of freedom from progression to more severe lymphedema was 79% at 1 year, 66% at 3 years, and 52% at 5 years. The patients who were morbidly obese, had positive axillary lymph nodes, or received supraclavicular irradiation at the time of breast cancer treatment were at higher risk of progression from mild arm lymphedema to more severe edema. Conclusions: Mild arm lymphedema, generally considered to be a minor complication after breast conservation treatment for breast cancer, was associated with a risk of progression to a more severe grade of arm lymphedema in a substantial fraction of patients.

  12. INNATE IMMUNITY. Cytosolic detection of the bacterial metabolite HBP activates TIFA-dependent innate immunity.

    PubMed

    Gaudet, Ryan G; Sintsova, Anna; Buckwalter, Carolyn M; Leung, Nelly; Cochrane, Alan; Li, Jianjun; Cox, Andrew D; Moffat, Jason; Gray-Owen, Scott D

    2015-06-12

    Host recognition of pathogen-associated molecular patterns (PAMPs) initiates an innate immune response that is critical for pathogen elimination and engagement of adaptive immunity. Here we show that mammalian cells can detect and respond to the bacterial-derived monosaccharide heptose-1,7-bisphosphate (HBP). A metabolic intermediate in lipopolysaccharide biosynthesis, HBP is highly conserved in Gram-negative bacteria, yet absent from eukaryotic cells. Detection of HBP within the host cytosol activated the nuclear facto κB pathway in vitro and induced innate and adaptive immune responses in vivo. Moreover, we used a genome-wide RNA interference screen to uncover an innate immune signaling axis, mediated by phosphorylation-dependent oligomerization of the TRAF-interacting protein with forkhead-associated domain (TIFA) that is triggered by HBP. Thus, HBP is a PAMP that activates TIFA-dependent immunity to Gram-negative bacteria.

  13. Predators, Prey and Habitat Structure: Can Key Conservation Areas and Early Signs of Population Collapse Be Detected in Neotropical Forests?

    PubMed Central

    de Thoisy, Benoit; Fayad, Ibrahim; Clément, Luc; Barrioz, Sébastien; Poirier, Eddy; Gond, Valéry

    2016-01-01

    Tropical forests with a low human population and absence of large-scale deforestation provide unique opportunities to study successful conservation strategies, which should be based on adequate monitoring tools. This study explored the conservation status of a large predator, the jaguar, considered an indicator of the maintenance of how well ecological processes are maintained. We implemented an original integrative approach, exploring successive ecosystem status proxies, from habitats and responses to threats of predators and their prey, to canopy structure and forest biomass. Niche modeling allowed identification of more suitable habitats, significantly related to canopy height and forest biomass. Capture/recapture methods showed that jaguar density was higher in habitats identified as more suitable by the niche model. Surveys of ungulates, large rodents and birds also showed higher density where jaguars were more abundant. Although jaguar density does not allow early detection of overall vertebrate community collapse, a decrease in the abundance of large terrestrial birds was noted as good first evidence of disturbance. The most promising tool comes from easily acquired LiDAR data and radar images: a decrease in canopy roughness was closely associated with the disturbance of forests and associated decreasing vertebrate biomass. This mixed approach, focusing on an apex predator, ecological modeling and remote-sensing information, not only helps detect early population declines in large mammals, but is also useful to discuss the relevance of large predators as indicators and the efficiency of conservation measures. It can also be easily extrapolated and adapted in a timely manner, since important open-source data are increasingly available and relevant for large-scale and real-time monitoring of biodiversity. PMID:27828993

  14. Predators, Prey and Habitat Structure: Can Key Conservation Areas and Early Signs of Population Collapse Be Detected in Neotropical Forests?

    PubMed

    de Thoisy, Benoit; Fayad, Ibrahim; Clément, Luc; Barrioz, Sébastien; Poirier, Eddy; Gond, Valéry

    2016-01-01

    Tropical forests with a low human population and absence of large-scale deforestation provide unique opportunities to study successful conservation strategies, which should be based on adequate monitoring tools. This study explored the conservation status of a large predator, the jaguar, considered an indicator of the maintenance of how well ecological processes are maintained. We implemented an original integrative approach, exploring successive ecosystem status proxies, from habitats and responses to threats of predators and their prey, to canopy structure and forest biomass. Niche modeling allowed identification of more suitable habitats, significantly related to canopy height and forest biomass. Capture/recapture methods showed that jaguar density was higher in habitats identified as more suitable by the niche model. Surveys of ungulates, large rodents and birds also showed higher density where jaguars were more abundant. Although jaguar density does not allow early detection of overall vertebrate community collapse, a decrease in the abundance of large terrestrial birds was noted as good first evidence of disturbance. The most promising tool comes from easily acquired LiDAR data and radar images: a decrease in canopy roughness was closely associated with the disturbance of forests and associated decreasing vertebrate biomass. This mixed approach, focusing on an apex predator, ecological modeling and remote-sensing information, not only helps detect early population declines in large mammals, but is also useful to discuss the relevance of large predators as indicators and the efficiency of conservation measures. It can also be easily extrapolated and adapted in a timely manner, since important open-source data are increasingly available and relevant for large-scale and real-time monitoring of biodiversity.

  15. Differential impact of fathers' authoritarian parenting on early adolescent adjustment in conservative protestant versus other families.

    PubMed

    Gunnoe, Marjorie Lindner; Hetherington, E Mavis; Reiss, David

    2006-12-01

    The purpose of the study was to determine whether well-established associations between authoritarian parenting and adolescent adjustment pertain to conservative Protestant (CP) families. Structural equation modeling was used to test paths from biological fathers' authoritarian parenting to adolescent adjustment in 65 CP versus 170 comparison families in the Nonshared Environment and Adolescent Development Study (NEAD; D. Reiss et al., 1994). The hypothesis that adolescents in CP families would be less harmed by authoritarian parenting than would adolescents in control families was partially supported: Authoritarian parenting directly predicted greater externalizing and internalizing for adolescents in control families but not for adolescents in CP families. In contrast, parents' religious affiliation failed to moderate the negative associations between authoritarian parenting and positive adjustment. Understanding family processes specific to the CP subculture is important for helping these families raise competent children.

  16. The Conserved Foot Domain of RNA Pol II Associates with Proteins Involved in Transcriptional Initiation and/or Early Elongation

    PubMed Central

    García-López, M. Carmen; Pelechano, Vicent; Mirón-García, M. Carmen; Garrido-Godino, Ana I.; García, Alicia; Calvo, Olga; Werner, Michel; Pérez-Ortín, José E.; Navarro, Francisco

    2011-01-01

    RNA polymerase (pol) II establishes many protein–protein interactions with transcriptional regulators to coordinate different steps of transcription. Although some of these interactions have been well described, little is known about the existence of RNA pol II regions involved in contact with transcriptional regulators. We hypothesize that conserved regions on the surface of RNA pol II contact transcriptional regulators. We identified such an RNA pol II conserved region that includes the majority of the “foot” domain and identified interactions of this region with Mvp1, a protein required for sorting proteins to the vacuole, and Spo14, a phospholipase D. Deletion of MVP1 and SPO14 affects the transcription of their target genes and increases phosphorylation of Ser5 in the carboxy-terminal domain (CTD). Genetic, phenotypic, and functional analyses point to a role for these proteins in transcriptional initiation and/or early elongation, consistent with their genetic interactions with CEG1, a guanylyltransferase subunit of the Saccharomyces cerevisiae capping enzyme. PMID:21954159

  17. The Restoration and Conservation of Egyptian Alabaster Vessels from the Early ERA in Atfiyah Museum Store - Helwan - Egypt

    NASA Astrophysics Data System (ADS)

    Radi Abdel Kader, R.; Sayed Mohamed, S.

    2013-07-01

    Egypt is considered one of the most countries which contain a lot of cultural heritage; the Ancient Egyptian used a lot of stones for his life like: limestone, sandstone, granite and Egyptian Alabaster. The Egyptian Alabaster is used for his daily and eternal life, he made a lot of funerary furniture from this stone like: vessels, statues, Architectural elements in the temples, tombs and canopic jars to preserve his viscera from decomposition like: stomach, liver … etc in the mummification process. Egyptian Alabaster is a sedimentary rock especially chemical- origin sedimentary rocks, it deposits inside caves and around springs which consists of calcium carbonates (CaCO3), they are very fragile "hardness = 3 in Mohs hardness scale". The Egyptian Alabaster vessels expose to a lot of deterioration factors in the burial and exposure environment after excavation. The study case vessels are made of Egyptian alabaster stone and belong to the early era (First and second Egyptian dynasties) in Atfiyah museum store, these vessels exposed to a lot of deterioration factors in the burial and exposure environment like: soil pressure, air temperature variety, relative humidity and salts. The vessels are conserved at the restoration laboratory in Atfiyah museum store by a lot of restoration and conservation processes like: cleaning - consolidation - assembling process for the separated parts and completion for the lost parts.

  18. EARLY BUD-BREAK1 (EBB1) defines a conserved mechanism for control of bud-break in woody perennials

    PubMed Central

    Busov, Victor; Carneros, Elena; Yakovlev, Igor

    2016-01-01

    Bud-break is an environmentally and economically important trait in trees, shrubs and vines from temperate latitudes. Poor synchronization of bud-break timing with local climates can lead to frost injuries, susceptibility to pests and pathogens and poor crop yields in fruit trees and vines. The rapid climate changes outpace the adaptive capacities of plants to respond through natural selection. This is particularly true for trees which have long generation cycle and thus the adaptive changes are significantly delayed. Therefore, to devise appropriate breeding and conservation strategies, it is imperative to understand the molecular underpinnings that govern dormancy mechanisms. We have recently identified and characterized the poplar EARLY BUD-BREAK 1 (EBB1) gene. EBB1 is a positive regulator of bud-break and encodes a transcription factor from the AP2/ERF family. Here, using comparative and functional genomics approaches we show that EBB1 function in regulation of bud-break is likely conserved across wide range of woody perennial species with importance to forestry and agriculture. PMID:26317150

  19. EARLY BUD-BREAK1 (EBB1) defines a conserved mechanism for control of bud-break in woody perennials.

    PubMed

    Busov, Victor; Carneros, Elena; Yakovlev, Igor

    2016-01-01

    Bud-break is an environmentally and economically important trait in trees, shrubs and vines from temperate latitudes. Poor synchronization of bud-break timing with local climates can lead to frost injuries, susceptibility to pests and pathogens and poor crop yields in fruit trees and vines. The rapid climate changes outpace the adaptive capacities of plants to respond through natural selection. This is particularly true for trees which have long generation cycle and thus the adaptive changes are significantly delayed. Therefore, to devise appropriate breeding and conservation strategies, it is imperative to understand the molecular underpinnings that govern dormancy mechanisms. We have recently identified and characterized the poplar EARLY BUD-BREAK 1 (EBB1) gene. EBB1 is a positive regulator of bud-break and encodes a transcription factor from the AP2/ERF family. Here, using comparative and functional genomics approaches we show that EBB1 function in regulation of bud-break is likely conserved across wide range of woody perennial species with importance to forestry and agriculture.

  20. Learning from the messengers: innate sensing of viruses and cytokine regulation of immunity - clues for treatments and vaccines.

    PubMed

    Melchjorsen, Jesper

    2013-01-31

    Virus infections are a major global public health concern, and only via substantial knowledge of virus pathogenesis and antiviral immune responses can we develop and improve medical treatments, and preventive and therapeutic vaccines. Innate immunity and the shaping of efficient early immune responses are essential for control of viral infections. In order to trigger an efficient antiviral defense, the host senses the invading microbe via pattern recognition receptors (PRRs), recognizing distinct conserved pathogen-associated molecular patterns (PAMPs). The innate sensing of the invading virus results in intracellular signal transduction and subsequent production of interferons (IFNs) and proinflammatory cytokines. Cytokines, including IFNs and chemokines, are vital molecules of antiviral defense regulating cell activation, differentiation of cells, and, not least, exerting direct antiviral effects. Cytokines shape and modulate the immune response and IFNs are principle antiviral mediators initiating antiviral response through induction of antiviral proteins. In the present review, I describe and discuss the current knowledge on early virus-host interactions, focusing on early recognition of virus infection and the resulting expression of type I and type III IFNs, proinflammatory cytokines, and intracellular antiviral mediators. In addition, the review elucidates how targeted stimulation of innate sensors, such as toll-like receptors (TLRs) and intracellular RNA and DNA sensors, may be used therapeutically. Moreover, I present and discuss data showing how current antimicrobial therapies, including antibiotics and antiviral medication, may interfere with, or improve, immune response.

  1. Resolution of deep angiosperm phylogeny using conserved nuclear genes and estimates of early divergence times

    PubMed Central

    Zeng, Liping; Zhang, Qiang; Sun, Renran; Kong, Hongzhi; Zhang, Ning; Ma, Hong

    2014-01-01

    Angiosperms are the most successful plants and support human livelihood and ecosystems. Angiosperm phylogeny is the foundation of studies of gene function and phenotypic evolution, divergence time estimation and biogeography. The relationship of the five divergent groups of the Mesangiospermae (~99.95% of extant angiosperms) remains uncertain, with multiple hypotheses reported in the literature. Here transcriptome data sets are obtained from 26 species lacking sequenced genomes, representing each of the five groups: eudicots, monocots, magnoliids, Chloranthaceae and Ceratophyllaceae. Phylogenetic analyses using 59 carefully selected low-copy nuclear genes resulted in highly supported relationships: sisterhood of eudicots and a clade containing Chloranthaceae and Ceratophyllaceae, with magnoliids being the next sister group, followed by monocots. Our topology allows a re-examination of the evolutionary patterns of 110 morphological characters. The molecular clock estimates of Mesangiospermae diversification during the late to middle Jurassic correspond well to the origins of some insects, which may have been a factor facilitating early angiosperm radiation. PMID:25249442

  2. Resolution of deep angiosperm phylogeny using conserved nuclear genes and estimates of early divergence times.

    PubMed

    Zeng, Liping; Zhang, Qiang; Sun, Renran; Kong, Hongzhi; Zhang, Ning; Ma, Hong

    2014-09-24

    Angiosperms are the most successful plants and support human livelihood and ecosystems. Angiosperm phylogeny is the foundation of studies of gene function and phenotypic evolution, divergence time estimation and biogeography. The relationship of the five divergent groups of the Mesangiospermae (~99.95% of extant angiosperms) remains uncertain, with multiple hypotheses reported in the literature. Here transcriptome data sets are obtained from 26 species lacking sequenced genomes, representing each of the five groups: eudicots, monocots, magnoliids, Chloranthaceae and Ceratophyllaceae. Phylogenetic analyses using 59 carefully selected low-copy nuclear genes resulted in highly supported relationships: sisterhood of eudicots and a clade containing Chloranthaceae and Ceratophyllaceae, with magnoliids being the next sister group, followed by monocots. Our topology allows a re-examination of the evolutionary patterns of 110 morphological characters. The molecular clock estimates of Mesangiospermae diversification during the late to middle Jurassic correspond well to the origins of some insects, which may have been a factor facilitating early angiosperm radiation.

  3. Yersinia pestis requires the 2-component regulatory system OmpR-EnvZ to resist innate immunity during the early and late stages of plague.

    PubMed

    Reboul, Angéline; Lemaître, Nadine; Titecat, Marie; Merchez, Maud; Deloison, Gaspard; Ricard, Isabelle; Pradel, Elizabeth; Marceau, Michaël; Sebbane, Florent

    2014-11-01

    Plague is transmitted by fleas or contaminated aerosols. To successfully produce disease, the causal agent (Yersinia pestis) must rapidly sense and respond to rapid variations in its environment. Here, we investigated the role of 2-component regulatory systems (2CSs) in plague because the latter are known to be key players in bacterial adaptation to environmental change. Along with the previously studied PhoP-PhoQ system, OmpR-EnvZ was the only one of Y. pestis' 23 other 2CSs required for production of bubonic, septicemic, and pneumonic plague. In vitro, OmpR-EnvZ was needed to counter serum complement and leukocytes but was not required for the secretion of antiphagocyte exotoxins. In vivo, Y. pestis lacking OmpR-EnvZ did not induce an early immune response in the skin and was fully virulent in neutropenic mice. We conclude that, throughout the course of Y. pestis infection, OmpR-EnvZ is required to counter toxic effectors secreted by polymorphonuclear leukocytes in the tissues.

  4. Adaptation in the innate immune system and heterologous innate immunity.

    PubMed

    Martin, Stefan F

    2014-11-01

    The innate immune system recognizes deviation from homeostasis caused by infectious or non-infectious assaults. The threshold for its activation seems to be established by a calibration process that includes sensing of microbial molecular patterns from commensal bacteria and of endogenous signals. It is becoming increasingly clear that adaptive features, a hallmark of the adaptive immune system, can also be identified in the innate immune system. Such adaptations can result in the manifestation of a primed state of immune and tissue cells with a decreased activation threshold. This keeps the system poised to react quickly. Moreover, the fact that the innate immune system recognizes a wide variety of danger signals via pattern recognition receptors that often activate the same signaling pathways allows for heterologous innate immune stimulation. This implies that, for example, the innate immune response to an infection can be modified by co-infections or other innate stimuli. This "design feature" of the innate immune system has many implications for our understanding of individual susceptibility to diseases or responsiveness to therapies and vaccinations. In this article, adaptive features of the innate immune system as well as heterologous innate immunity and their implications are discussed.

  5. Sexually dimorphic gene expressions in eels: useful markers for early sex assessment in a conservation context

    PubMed Central

    Geffroy, Benjamin; Guilbaud, Florian; Amilhat, Elsa; Beaulaton, Laurent; Vignon, Matthias; Huchet, Emmanuel; Rives, Jacques; Bobe, Julien; Fostier, Alexis; Guiguen, Yann; Bardonnet, Agnès

    2016-01-01

    Environmental sex determination (ESD) has been detected in a range of vertebrate reptile and fish species. Eels are characterized by an ESD that occurs relatively late, since sex cannot be histologically determined before individuals reach 28 cm. Because several eel species are at risk of extinction, assessing sex at the earliest stage is a crucial management issue. Based on preliminary results of RNA sequencing, we targeted genes susceptible to be differentially expressed between ovaries and testis at different stages of development. Using qPCR, we detected testis-specific expressions of dmrt1, amh, gsdf and pre-miR202 and ovary-specific expressions were obtained for zar1, zp3 and foxn5. We showed that gene expressions in the gonad of intersexual eels were quite similar to those of males, supporting the idea that intersexual eels represent a transitional stage towards testicular differentiation. To assess whether these genes would be effective early molecular markers, we sampled juvenile eels in two locations with highly skewed sex ratios. The combined expression of six of these genes allowed the discrimination of groups according to their potential future sex and thus this appears to be a useful tool to estimate sex ratios of undifferentiated juvenile eels. PMID:27658729

  6. VSG 117 gene is conservatively present and early expressed in Trypanosma evansi YNB stock.

    PubMed

    Jia, Yonggen; Guo, Liang; Zhao, Xinxin; Suo, Xun

    2012-05-01

    African trypanosomes, including Trypanosoma brucei and the closely related species Trypanosoma evansi, are flagellated unicellular parasites that proliferate extracellularly in the mammalian bloodstream and tissue spaces. They evade host immune system by periodically switching their variant surface glycoprotein (VSG) coat. Each trypanosome possesses a vast archive of VSGs with distinct sequence identity and different strains contain different archive of VSGs. VSG 117 was reported as a widespread VSG detected in the genomes of all the T. brucei strains. In this study, the presence and expression of VSG 117 gene was observed in T. evansi YNB stock by RT-PCR with VSG-specific primers. We further confirmed that this VSG tends to be expressed in the early stage of T. evansi infections (on day 12-15) by immuno-screening the previously isolated infected blood samples. It is possible that the VSG 117 gene evolved and spread through the African trypanosome population via genetic exchange, before T. evansi lost its ability to infect tsetse fly. Our finding provided an evidence of the close evolutionary relationship between T. evansi and T. brucei, in the terms of VSG genes.

  7. Sexually dimorphic gene expressions in eels: useful markers for early sex assessment in a conservation context

    NASA Astrophysics Data System (ADS)

    Geffroy, Benjamin; Guilbaud, Florian; Amilhat, Elsa; Beaulaton, Laurent; Vignon, Matthias; Huchet, Emmanuel; Rives, Jacques; Bobe, Julien; Fostier, Alexis; Guiguen, Yann; Bardonnet, Agnès

    2016-09-01

    Environmental sex determination (ESD) has been detected in a range of vertebrate reptile and fish species. Eels are characterized by an ESD that occurs relatively late, since sex cannot be histologically determined before individuals reach 28 cm. Because several eel species are at risk of extinction, assessing sex at the earliest stage is a crucial management issue. Based on preliminary results of RNA sequencing, we targeted genes susceptible to be differentially expressed between ovaries and testis at different stages of development. Using qPCR, we detected testis-specific expressions of dmrt1, amh, gsdf and pre-miR202 and ovary-specific expressions were obtained for zar1, zp3 and foxn5. We showed that gene expressions in the gonad of intersexual eels were quite similar to those of males, supporting the idea that intersexual eels represent a transitional stage towards testicular differentiation. To assess whether these genes would be effective early molecular markers, we sampled juvenile eels in two locations with highly skewed sex ratios. The combined expression of six of these genes allowed the discrimination of groups according to their potential future sex and thus this appears to be a useful tool to estimate sex ratios of undifferentiated juvenile eels.

  8. Cosmetic Outcome and Seroma Formation After Breast-Conserving Surgery With Intraoperative Radiation Therapy Boost for Early Breast Cancer

    SciTech Connect

    Senthi, Sashendra; Link, Emma; Chua, Boon H.

    2012-10-01

    Purpose: To evaluate cosmetic outcome and its association with breast wound seroma after breast-conserving surgery (BCS) with targeted intraoperative radiation therapy (tIORT) boost for early breast cancer. Methods and Materials: An analysis of a single-arm prospective study of 55 patients with early breast cancer treated with BCS and tIORT boost followed by conventional whole breast radiation therapy (WBRT) between August 2003 and January 2006 was performed. A seroma was defined as a fluid collection at the primary tumor resection site identified clinically or radiologically. Cosmetic assessments using the European Organization for Research and Treatment of Cancer rating system were performed at baseline before BCS and 30 months after WBRT was completed. Results: Twenty-eight patients (51%) developed a seroma, with 18 patients (33%) requiring at least 1 aspiration. Tumor location was significantly associated with seroma formation (P=.001). Ten of 11 patients with an upper inner quadrant tumor developed a seroma. Excellent or good overall cosmetic outcome at 30 months was observed in 34 patients (62%, 95% confidence interval 53%-80%). Seroma formation was not associated with the overall cosmetic result (P=.54). Conclusion: BCS with tIORT boost followed by WBRT was associated with an acceptable cosmetic outcome. Seroma formation was not significantly associated with an adverse cosmetic outcome.

  9. The innate and adaptive immune response to avian influenza virus infections and vaccines

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Protective immunity against viruses is mediated by the early innate immune responses and later on by the adaptive immune responses. The early innate immunity is designed to contain and limit virus replication in the host, primarily through cytokine and interferon production. Most all cells are cap...

  10. Cheetahs have a stronger constitutive innate immunity than leopards

    PubMed Central

    Heinrich, Sonja K.; Hofer, Heribert; Courtiol, Alexandre; Melzheimer, Jörg; Dehnhard, Martin; Czirják, Gábor Á.; Wachter, Bettina

    2017-01-01

    As a textbook case for the importance of genetics in conservation, absence of genetic variability at the major histocompatibility complex (MHC) is thought to endanger species viability, since it is considered crucial for pathogen resistance. An alternative view of the immune system inspired by life history theory posits that a strong response should evolve in other components of the immune system if there is little variation in the MHC. In contrast to the leopard (Panthera pardus), the cheetah (Acinonyx jubatus) has a relatively low genetic variability at the MHC, yet free-ranging cheetahs are healthy. By comparing the functional competence of the humoral immune system of both species in sympatric populations in Namibia, we demonstrate that cheetahs have a higher constitutive innate but lower induced innate and adaptive immunity than leopards. We conclude (1) immunocompetence of cheetahs is higher than previously thought; (2) studying both innate and adaptive components of immune systems will enrich conservation science. PMID:28333126

  11. Barrier to Autointegration Factor (BANF1): interwoven roles in nuclear structure, genome integrity, innate immunity, stress responses and progeria.

    PubMed

    Jamin, Augusta; Wiebe, Matthew S

    2015-06-01

    The Barrier to Autointegration Factor (BAF or BANF1) is an abundant, highly conserved DNA binding protein. BAF is involved in multiple pathways including mitosis, nuclear assembly, viral infection, chromatin and gene regulation and the DNA damage response. BAF is also essential for early development in metazoans and relevant to human physiology; BANF1 mutations cause a progeroid syndrome, placing BAF within the laminopathy disease spectrum. This review summarizes previous knowledge about BAF in the context of recent discoveries about its protein partners, posttranslational regulation, dynamic subcellular localizations and roles in disease, innate immunity, transposable elements and genome integrity.

  12. Barrier to Autointegration Factor (BANF1): interwoven roles in nuclear structure, genome integrity, innate immunity, stress responses and progeria

    PubMed Central

    Jamin, Augusta; Wiebe, Matthew S.

    2015-01-01

    The Barrier to Autointegration Factor (BAF or BANF1) is an abundant, highly conserved DNA binding protein. BAF is involved in multiple pathways including mitosis, nuclear assembly, viral infection, chromatin and gene regulation and the DNA damage response. BAF is also essential for early development in metazoans and relevant to human physiology; BANF1 mutations cause a progeroid syndrome, placing BAF within the laminopathy disease spectrum. This review summarizes previous knowledge about BAF in the context of recent discoveries about its protein partners, posttranslational regulation, dynamic subcellular localizations and roles in disease, innate immunity, transposable elements and genome integrity. PMID:26072104

  13. Evolutionary genetics of insect innate immunity

    PubMed Central

    2015-01-01

    Patterns of evolution in immune defense genes help to understand the evolutionary dynamics between hosts and pathogens. Multiple insect genomes have been sequenced, with many of them having annotated immune genes, which paves the way for a comparative genomic analysis of insect immunity. In this review, I summarize the current state of comparative and evolutionary genomics of insect innate immune defense. The focus is on the conserved and divergent components of immunity with an emphasis on gene family evolution and evolution at the sequence level; both population genetics and molecular evolution frameworks are considered. PMID:25750410

  14. Segment polarity gene expression in a myriapod reveals conserved and diverged aspects of early head patterning in arthropods.

    PubMed

    Janssen, Ralf

    2012-09-01

    Arthropods show two kinds of developmental mode. In the so-called long germ developmental mode (as exemplified by the fly Drosophila), all segments are formed almost simultaneously from a preexisting field of cells. In contrast, in the so-called short germ developmental mode (as exemplified by the vast majority of arthropods), only the anterior segments are patterned similarly as in Drosophila, and posterior segments are added in a single or double segmental periodicity from a posterior segment addition zone (SAZ). The addition of segments from the SAZ is controlled by dynamic waves of gene activity. Recent studies on a spider have revealed that a similar dynamic process, involving expression of the segment polarity gene (SPG) hedgehog (hh), is involved in the formation of the anterior head segments. The present study shows that in the myriapod Glomeris marginata the early expression of hh is also in a broad anterior domain, but this domain corresponds only to the ocular and antennal segment. It does not, like in spiders, represent expression in the posterior adjacent segment. In contrast, the anterior hh pattern is conserved in Glomeris and insects. All investigated myriapod SPGs and associated factors are expressed with delay in the premandibular (tritocerebral) segment. This delay is exclusively found in insects and myriapods, but not in chelicerates, crustaceans and onychophorans. Therefore, it may represent a synapomorphy uniting insects and myriapods (Atelocerata hypothesis), contradicting the leading opinion that suggests a sister relationship of crustaceans and insects (Pancrustacea hypothesis). In Glomeris embryos, the SPG engrailed is first expressed in the mandibular segment. This feature is conserved in representatives of all arthropod classes suggesting that the mandibular segment may have a special function in anterior patterning.

  15. Innate cellular immunity and xenotransplantation

    PubMed Central

    Wang, Hui; Yang, Yong-Guang

    2012-01-01

    Purpose of review This review assesses the recent progress in xenograft rejection by innate immune responses, with a focus on innate cellular xenoreactivity. Recent findings Current literature was reviewed for new insights into the role of innate cellular immunity in xenograft rejection. Increasing evidence confirms that vigorous innate immune cell activation is accounted for by a combination of xenoantigen recognition by activating receptors, and incompatibility in inhibitory receptor-ligand interactions. Although both innate humoral and cellular xenoimmune responses are predominantly elicited by preformed and induced xenoreactive antibodies in nonhuman primates following porcine xenotransplantation, innate immune cells can also be activated by xenografts in the absence of antibodies. The latter antibody-independent response will likely persist in recipients even when adaptive xenoimmune responses are suppressed. In addition to xenograft rejection by recipient innate immune cells, phagocytic cells within liver xenografts are also deleterious to recipients by causing thrombocytopenia. Summary Strategies of overcoming innate immune responses are required for successful clinical xenotransplantation. In addition to developing better immunosuppressive and tolerance induction protocols, endeavors towards further genetic modifications of porcine source animals are ultimately important for successful clinical xenotransplantation. PMID:22262106

  16. 'Conservation Education' and the Foundations of National Prosperity: Comparative Perspectives from Early Twentieth-Century North America and Britain.

    ERIC Educational Resources Information Center

    Marsden, William E.

    1998-01-01

    Compares the development of conservation education in North America and Britain. Reports that the focus of British conservation education was on preserving the countryside, while the United States focused on protecting natural resources. Finds that a major difference was that the label of 'conservation education' did not appear in Britain. (CMK)

  17. Innate microbial sensors and their relevance to allergy.

    PubMed

    Liu, Andrew H

    2008-11-01

    The innate immune system oversees the gateway to immunity with its microbial sensors. Innate microbial sensors are germ line-encoded receptors with genetically predetermined specificities for microbes. The readiness and effectiveness of the innate immune system to provide immediate and appropriate responses at the host-environment interface is dependent on its sensitive and comprehensive microbial detection systems. The purpose of this review is to provide an overview of innate microbial sensors, our growing understanding of their diverse repertoire, and their elegant structural and functional approaches to microbial recognition. Their relevance to allergic disease is also discussed: the potential recognition and uptake of allergens by some of these receptors, inhibited expression of other microbial sensors by allergic immune responses and inflammation, and their upregulation by microbial exposures in early life that may help to protect against the development of allergic immune responses and disease.

  18. Early ipsilateral breast tumor recurrences after breast conservation affect survival: An analysis of the National Cancer Institute randomized trial

    SciTech Connect

    Brooks, Joseph P.; Danforth, David N.; Albert, Paul; Sciuto, Linda C. B.S.N.; Smith, Sharon L.; Camphausen, Kevin A.; Poggi, Matthew M. . E-mail: MMPoggi@Bethesda.med.navy.mil

    2005-07-01

    Purpose: To evaluate the effect of an ipsilateral breast tumor recurrence (IBTR) after breast-conservation therapy (BCT) on survival. Methods and Materials: One hundred twenty-one women were randomized to BCT. Patients with an IBTR were analyzed to determine survival. Analysis was performed with Kaplan-Meier estimates, log-rank tests, and time-dependent covariate Cox models. Results: At a median follow-up of 18.4 years, 27 patients had an IBTR. The median survival time after IBTR was 13.1 years. The 5-year survival rate was 91.8% (95% confidence interval [CI], 81.5-100%). The 10-year survival rate was 54.3% (95% CI, 35.8-82.6%). According to a Cox model with time-dependent covariates, the hazard ratio or relative risk of dying for those with an IBTR at <5.3 years after BCT relative to patients without an IBTR after BCT is 1.47 (95% CI, 1.02-2.12%; p = 0.04). The hazard ratio for those who relapse after 5.3 years is 0.59 (95% CI, 0.22-1.61%; p = 0.31). Age at randomization, original tumor size, and the presence of positive regional nodes at initial presentation were not found to be associated with decreased survival. Conclusions: There seems to be a significant association of early IBTR after BCT with decreased survival. Local control should be maximized.

  19. Assessment of skin dose and its relation to cosmesis in the conservative treatment of early breast cancer

    SciTech Connect

    Habibollahi, F.; Mayles, H.M.; Mayles, W.P.; Winter, P.J.; Tong, D.; Fentiman, I.S.; Chaudary, M.A.; Hayward, J.L.

    1988-02-01

    A conservation technique has been developed for the treatment of early breast cancer which involved removal of the tumor, axillary clearance, tumor site implantation with Iridium-192 wires for a boost dose and subsequent treatment of the breast with radical megavoltage external beam therapy. Although the cosmetic results were satisfactory in the majority of the patients, for some it was rated as fair or poor. One variable factor which could have carried some morbidity was the dose of radiation received by the skin. In 51 patients, doses were measured at several points over the treated breast using Thermoluminescent Dosimetry (TLD) at the time of the iridium implant and during the subsequent external beam therapy. Development of skin pigmentation, edema, and fibrosis were unrelated to the dose received by the skin but the findings suggested that doses greater than 50 Gy to the skin increased the possibility of late (greater than 24 months) telangiectasia over the boosted area. Treatment of tumors in the lower half of the breast, or in large breasts, was associated with a higher incidence of poor cosmesis. This may have been the result of varying posture on the interstitial dose distribution from the Iridium-192 wires and comparison of dose distribution in both supine and erect positions was carried out.

  20. Tweaking Innate Immunity: the Promise of Innate Immunologicals As Anti-infectives

    PubMed Central

    Rosenthal, Kenneth L

    2006-01-01

    New and exciting insights into the importance of the innate immune system are revolutionizing our understanding of immune defense against infections, pathogenesis, and the treatment and prevention of infectious diseases. The innate immune system uses multiple families of germline-encoded pattern recognition receptors (PRRs) to detect infection and trigger a variety of antimicrobial defense mechanisms. PRRs are evolutionarily highly conserved and serve to detect infection by recognizing pathogen-associated molecular patterns that are unique to microorganisms and essential for their survival. Toll-like receptors (TLRs) are transmembrane signalling receptors that activate gene expression programs that result in the production of proinflammatory cytokines and chemokines, type I interferons and antimicrobial factors. Furthermore, TLR activation facilitates and guides activation of adaptive immune responses through the activation of dendritic cells. TLRs are localized on the cell surface and in endosomal/lysosomal compartments, where they detect bacterial and viral infections. In contrast, nucleotide-binding oligomerization domain proteins and RNA helicases are located in the cell cytoplasm, where they serve as intracellular PRRs to detect cytoplasmic infections, particularly viruses. Due to their ability to enhance innate immune responses, novel strategies to use ligands, synthetic agonists or antagonists of PRRs (also known as ‘innate immunologicals’) can be used as stand-alone agents to provide immediate protection or treatment against bacterial, viral or parasitic infections. Furthermore, the newly appreciated importance of innate immunity in initiating and shaping adaptive immune responses is contributing to our understanding of vaccine adjuvants and promises to lead to improved next-generation vaccines. PMID:18382644

  1. Innate Immune Evasion by Filoviruses

    PubMed Central

    Basler, Christopher F.

    2015-01-01

    Ebola viruses and Marburg viruses, members of the filovirus family, cause severe hemorrhagic fever. The ability of these viruses to potently counteract host innate immune responses is thought to be an important component of viral pathogenesis. Several mechanisms of filoviral innate immune evasion have been defined and are reviewed here. These mechanisms inclue suppression of type I interferon (IFN) production; inhibition of IFN-signaling and mechanisms that either prevent cell stress responses or allow the virus to replication in the face of such responses. A greater understanding these innate immune evasion mechanisms may suggest novel therapeutic approaches for these deadly pathogens. PMID:25843618

  2. Similar Survival With Breast Conservation Therapy or Mastectomy in the Management of Young Women With Early-Stage Breast Cancer

    SciTech Connect

    Mahmood, Usama; Morris, Christopher; Neuner, Geoffrey; Koshy, Matthew; Kesmodel, Susan; Buras, Robert; Chumsri, Saranya; Bao Ting; Tkaczuk, Katherine; Feigenberg, Steven

    2012-08-01

    Purpose: To evaluate survival outcomes of young women with early-stage breast cancer treated with breast conservation therapy (BCT) or mastectomy, using a large, population-based database. Methods and Materials: Using the Surveillance, Epidemiology, and End Results (SEER) database, information was obtained for all female patients, ages 20 to 39 years old, diagnosed with T1-2 N0-1 M0 breast cancer between 1990 and 2007, who underwent either BCT (lumpectomy and radiation treatment) or mastectomy. Multivariable and matched pair analyses were performed to compare overall survival (OS) and cause-specific survival (CSS) of patients undergoing BCT and mastectomy. Results: A total of 14,764 women were identified, of whom 45% received BCT and 55% received mastectomy. Median follow-up was 5.7 years (range, 0.5-17.9 years). After we accounted for all patient and tumor characteristics, multivariable analysis found that BCT resulted in OS (hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.83-1.04; p = 0.16) and CSS (HR, 0.93; CI, 0.83-1.05; p = 0.26) similar to that of mastectomy. Matched pair analysis, including 4,644 BCT and mastectomy patients, confirmed no difference in OS or CSS: the 5-, 10-, and15-year OS rates for BCT and mastectomy were 92.5%, 83.5%, and 77.0% and 91.9%, 83.6%, and 79.1%, respectively (p = 0.99), and the 5-, 10-, and 15-year CSS rates for BCT and mastectomy were 93.3%, 85.5%, and 79.9% and 92.5%, 85.5%, and 81.9%, respectively (p = 0.88). Conclusions: Our analysis of this population-based database suggests that young women with early-stage breast cancer have similar survival rates whether treated with BCT or mastectomy. These patients should be counseled appropriately regarding their treatment options and should not choose a mastectomy based on the assumption of improved survival.

  3. The Association of Hepatitis C Virus Glycoproteins with Apolipoproteins E and B Early in Assembly Is Conserved in Lipoviral Particles*

    PubMed Central

    Boyer, Audrey; Dumans, Amélie; Beaumont, Elodie; Etienne, Loïc; Roingeard, Philippe; Meunier, Jean-Christophe

    2014-01-01

    In patients chronically infected with hepatitis C virus and in the HCV cell culture system (HCVcc), it is known that highly infectious virus particles have low to very low buoyant densities. These low densities have been attributed to the association of HCV with lipoprotein components, which occur during the viral morphogenesis. The resulting hybrid particles are known as lipoviral particles (LVP); however, very little is known about how these particles are created. In our study, we used Huh7.5 cells to investigate the intracellular association between envelope proteins and apolipoproteins B and E (ApoB and ApoE, respectively). In particular, we were interested in the role of this association in initiating LVP morphogenesis. Co-immunoprecipitation assays revealed that ApoB, ApoE, and HCV glycoproteins formed a protein complex early in the HCV lifecycle. Confocal analyses of naïve, E1E2-transduced and HCVcc-infected cells showed that HCV glycoproteins, ApoB and ApoE were found strongly colocalized only in the endoplasmic reticulum. We also found that HCV glycoproteins, ApoB and ApoE were already associated with intracellular infectious viral particles and, furthermore, that the protein complex was conserved in the infectious viral particles present in the supernatant of infected Huh7.5 cells. The association of HCV glycoproteins with ApoE was also evidenced in the HCVpp system, using the non-hepatic HEK293T cell line. We suggest that the complex formed by HCV E1E2, ApoB, and ApoE may initiate lipoviral particle morphogenesis. PMID:24838241

  4. The Prognostic Impact of Molecular Subtypes and Very Young Age on Breast Conserving Surgery in Early Stage Breast Cancer

    PubMed Central

    McGuire, Kandace; Alco, Gul; Nur Pilanci, Kezban; Koksal, Ulkuhan I; Elbüken, Filiz; Erdogan, Zeynep; Agacayak, Filiz; Ilgun, Serkan; Sarsenov, Dauren; Öztürk, Alper; İğdem, Şefik; Okkan, Sait; Eralp, Yeşim; Dincer, Maktav; Ozmen, Vahit

    2016-01-01

    Background Premenopausal breast cancer with a triple-negative phenotype (TNBC) has been associated with inferior locoregional recurrence free survival (LRFS) and overall survival (OS) after breast conserving surgery (BCS). The aim of this study is to analyze the association between age, subtype, and surgical treatment on survival in young women (≤40 years) with early breast cancer in a population with a high rate of breast cancer in young women. Methods Three hundred thirty-two patients ≤40 years old with stage I-II invasive breast cancer who underwent surgery at a single institution between 1998 and 2012 were identified retrospectively. Uni- and multivariate analysis evaluated predictors of LRFS, OS, and disease free survival (DFS). Results Most patients (64.2%) underwent BCS. Mean age and follow-up time were 35 (25 ± 3.61) years, and 72 months (range, 24–252), respectively. In multivariate analysis, multicentricity/multifocality and young age (<35 years) independently predicted for poorer DFS and OS. Those aged 35–40 years had higher LRFS and DFS than those <35 in the mastectomy group (p=0.007 and p=0.039, respectively). Patients with TNBC had lower OS compared with patients with luminal A subtype (p=0.042), and those who underwent BCS had higher OS than patients after mastectomy (p=0.015). Conclusion Young age (< 35 years) is an independent predictor of poorer OS and DFS as compared with ages 35–40, even in countries with a lower average age of breast cancer presentation. In addition, TNBC in the young predicts for poorer OS. BCS can be performed in young patients with TNBC, despite their poorer overall survival. PMID:27433412

  5. Is matching innate?

    PubMed

    Gallistel, C R; King, Adam Philip; Gottlieb, Daniel; Balci, Fuat; Papachristos, Efstathios B; Szalecki, Matthew; Carbone, Kimberly S

    2007-03-01

    Experimentally naive mice matched the proportions of their temporal investments (visit durations) in two feeding hoppers to the proportions of the food income (pellets per unit session time) derived from them in three experiments that varied the coupling between the behavioral investment and food income, from no coupling to strict coupling. Matching was observed from the outset; it did not improve with training. When the numbers of pellets received were proportional to time invested, investment was unstable, swinging abruptly from sustained, almost complete investment in one hopper, to sustained, almost complete investment in the other-in the absence of appropriate local fluctuations in returns (pellets obtained per time invested). The abruptness of the swings strongly constrains possible models. We suggest that matching reflects an innate (unconditioned) program that matches the ratio of expected visit durations to the ratio between the current estimates of expected incomes. A model that processes the income stream looking for changes in the income and generates discontinuous income estimates when a change is detected is shown to account for salient features of the data.

  6. Habitat odor can alleviate innate stress responses in mice.

    PubMed

    Matsukawa, Mutsumi; Imada, Masato; Aizawa, Shin; Sato, Takaaki

    2016-01-15

    Predatory odors, which can induce innate fear and stress responses in prey species, are frequently used in the development of animal models for several psychiatric diseases including post-traumatic stress disorder (PTSD) following a life-threatening event. We have previously shown that odors can be divided into at least three types; odors that act as (1) innate stressors, (2) as innate relaxants, or (3) have no innate effects on stress responses. Here, we attempted to verify whether an artificial odor, which had no innate effect on predatory odor-induced stress, could alleviate stress if experienced in early life as a habitat odor. In the current study, we demonstrated that the innate responses were changed to counteract stress following a postnatal experience. Moreover, we suggest that inhibitory circuits involved in stress-related neuronal networks and the concentrations of norepinephrine in the hippocampus may be crucial in alleviating stress induced by the predatory odor. Overall, these findings may be important for understanding the mechanisms involved in differential odor responses and also for the development of pharmacotherapeutic interventions that can alleviate stress in illnesses like PTSD.

  7. Bridging innate and adaptive immunity.

    PubMed

    Paul, William E

    2011-12-09

    The Nobel Prize in Physiology or Medicine for 2011 to Jules Hoffmann, Bruce Beutler, and the late Ralph Steinman recognizes accomplishments in understanding and unifying the two strands of immunology, the evolutionarily ancient innate immune response and modern adaptive immunity.

  8. Cover crop management practices-implications for early season weed control in conservation tillage corn cotton rotation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Use of the winter cover crops is an integral component of the conservation systems in corn (Zea mays L.) and cotton (Gossypium hirsutum L.). A field experiment was initiated in 2004 to evaluate weed suppression provided by winter cover crops in a conservation tillage corn and cotton rotation. Rotati...

  9. Innate Immune Defenses in Human Tuberculosis: An Overview of the Interactions between Mycobacterium tuberculosis and Innate Immune Cells

    PubMed Central

    Sia, Jonathan Kevin; Georgieva, Maria; Rengarajan, Jyothi

    2015-01-01

    Tuberculosis (TB) remains a serious global public health problem that results in up to 2 million deaths each year. TB is caused by the human pathogen, Mycobacterium tuberculosis (Mtb), which infects primarily innate immune cells patrolling the lung. Innate immune cells serve as barometers of the immune response against Mtb infection by determining the inflammatory milieu in the lungs and promoting the generation of adaptive immune responses. However, innate immune cells are also potential niches for bacterial replication and are readily manipulated by Mtb. Our understanding of the early interactions between Mtb and innate immune cells is limited, especially in the context of human infection. This review will focus on Mtb interactions with human macrophages, dendritic cells, neutrophils, and NK cells and detail evidence that Mtb modulation of these cells negatively impacts Mtb-specific immune responses. Furthermore, this review will emphasize important innate immune pathways uncovered through human immunogenetic studies. Insights into the human innate immune response to Mtb infection are necessary for providing a rational basis for the augmentation of immune responses against Mtb infection, especially with respect to the generation of effective anti-TB immunotherapeutics and vaccines. PMID:26258152

  10. Innate Immune Defenses in Human Tuberculosis: An Overview of the Interactions between Mycobacterium tuberculosis and Innate Immune Cells.

    PubMed

    Sia, Jonathan Kevin; Georgieva, Maria; Rengarajan, Jyothi

    2015-01-01

    Tuberculosis (TB) remains a serious global public health problem that results in up to 2 million deaths each year. TB is caused by the human pathogen, Mycobacterium tuberculosis (Mtb), which infects primarily innate immune cells patrolling the lung. Innate immune cells serve as barometers of the immune response against Mtb infection by determining the inflammatory milieu in the lungs and promoting the generation of adaptive immune responses. However, innate immune cells are also potential niches for bacterial replication and are readily manipulated by Mtb. Our understanding of the early interactions between Mtb and innate immune cells is limited, especially in the context of human infection. This review will focus on Mtb interactions with human macrophages, dendritic cells, neutrophils, and NK cells and detail evidence that Mtb modulation of these cells negatively impacts Mtb-specific immune responses. Furthermore, this review will emphasize important innate immune pathways uncovered through human immunogenetic studies. Insights into the human innate immune response to Mtb infection are necessary for providing a rational basis for the augmentation of immune responses against Mtb infection, especially with respect to the generation of effective anti-TB immunotherapeutics and vaccines.

  11. A role for innate immunity in type 1 diabetes?

    PubMed

    Beyan, H; Buckley, L R; Yousaf, N; Londei, M; Leslie, R D G

    2003-01-01

    Two arms of the immune system, innate and adaptive immunity, differ in their mode of immune recognition. The innate immune system recognizes a few highly conserved structures on a broad range of microorganisms. On the other hand, recognition of self or autoreactivity is generally confined to the adaptive immune response. Whilst autoimmune features are relatively common, they should be distinguished from autoimmune disease that is infrequent. Type 1 diabetes is an immune-mediated disease due to the destruction of insulin secreting cells mediated by aggressive immune responses, including activation of the adaptive immune system following genetic and environmental interaction. Hypotheses for the cause of the immune dysfunction leading to type 1 diabetes include self-reactive T-cell clones that (1) escape deletion in the thymus, (2) escape from peripheral tolerance or (3) escape from homeostatic control with an alteration in the immune balance leading to autoimmunity. Evidence, outlined in this review, raises the possibility that changes in the innate immune system could lead to autoimmunity, by either priming or promoting aggressive adaptive immune responses. Hostile microorganisms are identified by genetically determined surface receptors on innate effector cells, thereby promoting clearance of these invaders. These innate effectors include a few relatively inflexible cell populations such as monocytes/macrophages, dendritic cells (DC), natural killer (NK) cells, natural killer T (NKT) cells and gammadelta T cells. Recent studies have identified abnormalities in some of these cells both in patients with type 1 diabetes and in those at risk of the disease. However, it remains unclear whether these abnormalities in innate effector cells predispose to autoimmune disease. If they were to do so, then modulation of the innate immune system could be of therapeutic value in preventing immune-mediated diseases such as type 1 diabetes.

  12. The role of innate immunity in donor organ procurement.

    PubMed

    McKay, Dianne B

    2011-03-01

    Solid organ transplantation is a life saving procedure for patients with end-stage organ disease, and great care is taken to ensure that healthy organs are procured from deceased or live donors. Despite rigorous efforts to avoid injury, all organs experience some degree of damage from a process called ischemia reperfusion injury (IRI). The first part of the injury (ischemia) occurs when the donor organ's blood supply is compromised, and the second part (reperfusion) occurs when the blood supply is reestablished. The pathophysiology of the IRI is complex, but data from many laboratories have demonstrated that the inciting events of ischemia/reperfusion injury are triggered through a phylogenetically conserved system called the innate immune system. The innate immune system is a complex array of molecules, receptors and cellular elements present in species as diverse as plants to humans. This review discusses the role of the innate immune system in renal IRI and focuses on mechanisms of injury during organ procurement and transplantation. Although there are overlapping complex mechanisms, blockade of the innate immune system will likely provide a novel approach to preventing the earliest events associated with renal ischemia. Potentially, blockade of innate immune activation will provide the opportunity to increase the use marginal donors, especially those from patients deceased after cardiac death.

  13. A pilot study to investigate the role of the 26S proteasome in radiotherapy resistance and loco-regional recurrence following breast conserving therapy for early breast cancer.

    PubMed

    Elfadl, Dalia; Hodgkinson, Victoria C; Long, Ervine D; Scaife, Lucy; Drew, Philip J; Lind, Michael J; Cawkwell, Lynn

    2011-08-01

    Breast conserving therapy is a currently accepted method for managing patients with early stage breast cancer. However, approximately 7% of patients may develop loco-regional tumour recurrence within 5 years. We previously reported that expression of the 26S proteasome may be associated with radio-resistance. Here we aimed to analyse the 26S proteasome in a pilot series of early breast cancers and correlate the findings with loco-regional recurrence. Fourteen patients with early breast cancer who developed loco-regional recurrence within 4 years of completing breast conserving therapy were selected according to strict criteria and compared with those from 14 patients who were disease-free at 10 years. Decreased expression of the 26S proteasome was significantly associated with radio-resistance, manifested as the development of a loco-regional recurrence within 4 years of breast conserving therapy (p = 0.018). This small pilot study provides further suggestion that the 26S proteasome may be associated with response to radiotherapy.

  14. Pattern Recognition Receptors in Innate Immunity, Host Defense, and Immunopathology

    ERIC Educational Resources Information Center

    Suresh, Rahul; Mosser, David M.

    2013-01-01

    Infection by pathogenic microbes initiates a set of complex interactions between the pathogen and the host mediated by pattern recognition receptors. Innate immune responses play direct roles in host defense during the early stages of infection, and they also exert a profound influence on the generation of the adaptive immune responses that ensue.…

  15. Innate immunity in allergic disease.

    PubMed

    Minnicozzi, Michael; Sawyer, Richard T; Fenton, Matthew J

    2011-07-01

    The innate immune system consists of multiple cell types that express germline-encoded pattern recognition receptors that recognize pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Allergens are frequently found in forms and mixtures that contain PAMPs and DAMPs. The innate immune system is interposed between the external environment and the internal acquired immune system. It is also an integral part of the airways, gut, and skin. These tissues face continuous exposure to allergens, PAMPs, and DAMPs. Interaction of allergens with the innate immune system normally results in immune tolerance but, in the case of allergic disease, this interaction induces recurring and/or chronic inflammation as well as the loss of immunologic tolerance. Upon activation by allergens, the innate immune response commits the acquired immune response to a variety of outcomes mediated by distinct T-cell subsets, such as T-helper 2, regulatory T, or T-helper 17 cells. New studies highlighted in this review underscore the close relationship between allergens, the innate immune system, and the acquired immune system that promotes homeostasis versus allergic disease.

  16. Innate immune recognition of cancer.

    PubMed

    Woo, Seng-Ryong; Corrales, Leticia; Gajewski, Thomas F

    2015-01-01

    The observation that a subset of cancer patients show evidence for spontaneous CD8+ T cell priming against tumor-associated antigens has generated renewed interest in the innate immune pathways that might serve as a bridge to an adaptive immune response to tumors. Manipulation of this endogenous T cell response with therapeutic intent-for example, using blocking antibodies inhibiting PD-1/PD-L1 (programmed death-1/programmed death ligand 1) interactions-is showing impressive clinical results. As such, understanding the innate immune mechanisms that enable this T cell response has important clinical relevance. Defined innate immune interactions in the cancer context include recognition by innate cell populations (NK cells, NKT cells, and γδ T cells) and also by dendritic cells and macrophages in response to damage-associated molecular patterns (DAMPs). Recent evidence has indicated that the major DAMP driving host antitumor immune responses is tumor-derived DNA, sensed by the stimulator of interferon gene (STING) pathway and driving type I IFN production. A deeper knowledge of the clinically relevant innate immune pathways involved in the recognition of tumors is leading toward new therapeutic strategies for cancer treatment.

  17. Sweeten PAMPs: Role of Sugar Complexed PAMPs in Innate Immunity and Vaccine Biology

    PubMed Central

    Mahla, Ranjeet Singh; Reddy, Madhava C.; Prasad, D. Vijaya Raghava; Kumar, Himanshu

    2013-01-01

    Innate sensors play a critical role in the early innate immune responses to invading pathogens through sensing of diverse biochemical signatures also known as pathogen associated molecular patterns (PAMPs). These biochemical signatures primarily consist of a major family of biomolecules such as proteins, lipids, nitrogen bases, and sugar and its complexes, which are distinct from host molecules and exclusively expressed in pathogens and essential to their survival. The family of sensors known as pattern recognition receptors (PRRs) are germ-line encoded, evolutionarily conserved molecules, and consist of Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), NOD-like receptors (NLRs), C-type lectin-like receptors (CLRs), and DNA sensors. Sensing of PAMP by PRR initiates the cascade of signaling leading to the activation of transcription factors, such as NF-κB and interferon regulatory factors (IRFs), resulting in a variety of cellular responses, including the production of interferons (IFNs) and pro-inflammatory cytokines. In this review, we discuss sensing of different types of glycosylated PAMPs such as β-glucan (a polymeric sugar) or lipopolysaccharides, nucleic acid, and so on (sugar complex PAMPs) by different families of sensors, its role in pathogenesis, and its application in development of potential vaccine and vaccine adjuvants. PMID:24032031

  18. Bacterial and fungal pattern recognition receptors in homologous innate signaling pathways of insects and mammals

    PubMed Central

    Stokes, Bethany A.; Yadav, Shruti; Shokal, Upasana; Smith, L. C.; Eleftherianos, Ioannis

    2015-01-01

    In response to bacterial and fungal infections in insects and mammals, distinct families of innate immune pattern recognition receptors (PRRs) initiate highly complex intracellular signaling cascades. Those cascades induce a variety of immune functions that restrain the spread of microbes in the host. Insect and mammalian innate immune receptors include molecules that recognize conserved microbial molecular patterns. Innate immune recognition leads to the recruitment of adaptor molecules forming multi-protein complexes that include kinases, transcription factors, and other regulatory molecules. Innate immune signaling cascades induce the expression of genes encoding antimicrobial peptides and other key factors that mount and regulate the immune response against microbial challenge. In this review, we summarize our current understanding of the bacterial and fungal PRRs for homologous innate signaling pathways of insects and mammals in an effort to provide a framework for future studies. PMID:25674081

  19. GPCRs in invertebrate innate immunity.

    PubMed

    Reboul, Jerome; Ewbank, Jonathan J

    2016-08-15

    G-protein coupled receptors (GPCRs) represent a privileged point of contact between cells and their surrounding environment. They have been widely adopted in vertebrates as mediators of signals involved in both innate and adaptive immunity. Invertebrates rely on innate immune defences to resist infection. We review here evidence from a number of different species, principally the genetically tractable Caenorhabditis elegans and Drosophila melanogaster that points to an important role for GPCRs in modulating innate immunity in invertebrates too. In addition to examples of GPCRs involved in regulating the expression of defence genes, we discuss studies in C. elegans addressing the role of GPCR signalling in pathogen aversive behaviour. Despite the many lacunae in our current knowledge, it is clear that GPCR signalling contributes to host defence across the animal kingdom.

  20. Cancer Immunosurveillance by Tissue-resident Innate Lymphoid Cells and Innate-like T Cells

    PubMed Central

    Dadi, Saïda; Chhangawala, Sagar; Whitlock, Benjamin M.; Franklin, Ruth A.; Luo, Chong T.; Oh, Soyoung A.; Toure, Ahmed; Pritykin, Yuri; Huse, Morgan; Leslie, Christina S.; Li, Ming O.

    2016-01-01

    Summary Malignancy can be suppressed by the immune system in a process termed immunosurveillance. However, to what extent immunosurveillance occurs in spontaneous cancers and the composition of participating cell types remain obscure. Here we show that cell transformation triggers a tissue-resident lymphocyte response in oncogene-induced murine cancer models. Non-circulating cytotoxic lymphocytes, derived from innate, TCRαβ and TCRγδ lineages, expand in early tumors. Characterized by high expression of NK1.1, CD49a and CD103, these cells share a gene expression signature distinct from those of conventional NK cells, T cells and invariant NKT cells. Generation of these lymphocytes is dependent on the cytokine IL-15, but not the transcription factor Nfil3 that is required for the differentiation of tumor-infiltrating NK cells, and IL-15, but not Nfil3, deficiency results in accelerated tumor growth. These findings reveal a tumor-elicited immunosurveillance mechanism that engages unconventional type 1-like innate lymphoid cells and type 1 innate-like T cells. PMID:26806130

  1. Role of the innate immune system in acute viral myocarditis.

    PubMed

    Huang, Chien-Hua; Vallejo, Jesus G; Kollias, George; Mann, Douglas L

    2009-05-01

    Although the adaptive immune system is thought to play an important role in the pathogenesis of viral myocarditis, the role of the innate immune system has not been well defined. To address this deficiency, we employed a unique line of mice that harbor a genomic "knock in" of a mutated TNF gene lacking the AU rich element (TNF(ARE/ARE)) that is critical for TNF mRNA stability and translation, in order to examine the contribution of the innate immune system in encephalomyocarditis-induced myocarditis (EMCV). Heterozygous mice (TNF(ARE/+)) were infected with 500 plaque-forming units of EMCV. TNF(ARE/+)mice had a significantly higher 14-day mortality and myocardial inflammation when compared to littermate control mice. Virologic studies showed that the viral load at 14 days was significantly lower in the hearts of TNF(ARE/+) mice. TNF(ARE/+) mice had an exaggerated proinflammatory cytokine and chemokine response in the heart following EMCV infection. Modulation of the innate immune response in TNF(ARE/+) mice by the late administration of prednisolone resulted in a significant improvement in survival and decreased cardiac inflammation, whereas early administration of prednisolone resulted in a blunted innate response and increased mortality in littermate control mice. Viewed together, these data suggest that the duration and degree of activation of the innate immune system plays a critical role in determining host outcomes in experimental viral myocarditis.

  2. Evolution of innate-like T cells and their selection by MHC class I-like molecules.

    PubMed

    Edholm, Eva-Stina; Banach, Maureen; Robert, Jacques

    2016-08-01

    Until recently, major histocompatibility complex (MHC) class I-like-restricted innate-like αβT (iT) cells expressing an invariant or semi-invariant T cell receptor (TCR) repertoire were thought to be a recent evolutionary acquisition restricted to mammals. However, molecular and functional studies in Xenopus laevis have demonstrated that iT cells, defined as MHC class I-like-restricted innate-like αβT cells with a semi-invariant TCR, are evolutionarily conserved and prominent from early development in amphibians. As these iT cells lack the specificity conferred by conventional αβ TCRs, it is generally considered that they are specialized to recognize conserved antigens equivalent to pathogen-associated molecular patterns. Thus, one advantage offered by the MHC class I-like iT cell-based recognition system is that it can be adapted to a common pathogen and function on the basis of a relatively small number of T cells. Although iT cells have only been functionally described in mammals and amphibians, the identification of non-classical MHC/MHC class I-like genes in other groups of endothermic and ectothermic vertebrates suggests that iT cells have a broader phylogenetic distribution than previously envisioned. In this review, we discuss the possible role of iT cells during the emergence of the jawed vertebrate adaptive immune system.

  3. The highly conserved aspartic acid residue between hypervariable regions 1 and 2 of human immunodeficiency virus type 1 gp120 is important for early stages of virus replication.

    PubMed Central

    Wang, W K; Essex, M; Lee, T H

    1995-01-01

    Between hypervariable regions V1 and V2 of human immunodeficiency virus type 1 (HIV-1) gp120 lies a cluster of relatively conserved residues. The contribution of nine charged residues in this region to virus infectivity was evaluated by single-amino-acid substitutions in an infectious provirus clone. Three of the HIV-1 mutants studied had slower growth kinetics than the wild-type virus. The delay was most pronounced in a mutant with an alanine substituted for an aspartic acid residue at position 180. This aspartic acid is conserved by all HIV-1 isolates with known nucleotide sequences. Substitutions with three other residues at this position, including a negatively charged glutamic acid, all affected virus infectivity. The defect identified in these mutants suggests that this aspartic acid residue is involved in the early stages of HIV-1 replication. PMID:7983752

  4. [Perinatal innate immune activation and neuropsychological development].

    PubMed

    Nagai, Taku

    2013-08-01

    Development of animal models is a crucial issue in biological psychiatry for the search of novel drug targets as well as the screening of candidate compounds. Epidemiologic studies suggest that environmental insults, such as prenatal infection and perinatal complication, are involved in the development of schizophrenia. Recently, we have developed a novel mouse model of viral infection during the perinatal stage by injecting polyriboinosinic-polyribocytidilic acid (polyI:C) into neonatal mice. Neonatal treatment of mice with polyI:C, an inducer of innate immune responses via toll-like receptor 3, caused a significant increase in interferon-induced transmembrane protein 3 (IFITM3) levels in the astrocytes of the hippocampus, which resulted in long-lasting brain dysfunction, including cognitive and emotional impairments as well as a deficit in depolarization-evoked glutamate release in the hippocampus in adulthood. Neonatal polyI:C-induced neuronal impairments have not been observed in IFITM3-KO mice. These findings suggest that the induction of IFITM3 expression in astrocytes by the activation of the innate immune system during the early stages of neurodevelopment has non-cell autonomous effects that affect subsequent neurodevelopment, leading to neuropathological impairments and brain dysfunction, by impairing endocytosis in astrocytes.

  5. Dual antibody therapy to harness the innate anti-tumor immune response to enhance antibody targeting of tumors.

    PubMed

    Chester, Cariad; Marabelle, Aurelien; Houot, Roch; Kohrt, Holbrook E

    2015-04-01

    Cancer immunotherapy is a rapidly evolving field that offers a novel paradigm for cancer treatment: therapies focus on enhancing the immune system's innate and adaptive anti-tumor response. Early immunotherapeutics have achieved impressive clinical outcomes and monoclonal antibodies are now integral to therapeutic strategies in a variety of cancers. However, only recently have antibodies targeting innate immune cells entered clinical development. Innate immune effector cells play important roles in generating and maintaining antitumor immunity. Antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) are important innate immune mechanisms for tumor eradication. These cytolytic processes are initiated by the detection of a tumor-targeting antibody and can be augmented by activating co-stimulatory pathways or blocking inhibitory signals on innate immune cells. The combination of FDA-approved monoclonal antibodies with innate effector-targeting antibodies has demonstrated potent preclinical therapeutic synergy and early-phase combinatorial clinical trials are ongoing.

  6. Management of the Regional Lymph Nodes Following Breast-Conservation Therapy for Early-Stage Breast Cancer: An Evolving Paradigm

    SciTech Connect

    Warren, Laura E.G.; Punglia, Rinaa S.; Wong, Julia S.; Bellon, Jennifer R.

    2014-11-15

    Radiation therapy to the breast following breast conservation surgery has been the standard of care since randomized trials demonstrated equivalent survival compared to mastectomy and improved local control and survival compared to breast conservation surgery alone. Recent controversies regarding adjuvant radiation therapy have included the potential role of additional radiation to the regional lymph nodes. This review summarizes the evolution of regional nodal management focusing on 2 topics: first, the changing paradigm with regard to surgical evaluation of the axilla; second, the role for regional lymph node irradiation and optimal design of treatment fields. Contemporary data reaffirm prior studies showing that complete axillary dissection may not provide additional benefit relative to sentinel lymph node biopsy in select patient populations. Preliminary data also suggest that directed nodal radiation therapy to the supraclavicular and internal mammary lymph nodes may prove beneficial; publication of several studies are awaited to confirm these results and to help define subgroups with the greatest likelihood of benefit.

  7. Evolution of innate and adaptive immune systems in jawless vertebrates.

    PubMed

    Kasamatsu, Jun

    2013-01-01

    Because jawless vertebrates are the most primitive vertebrates, they have been studied to gain understanding of the evolutionary processes that gave rise to the innate and adaptive immune systems in vertebrates. Jawless vertebrates have developed lymphocyte-like cells that morphologically resemble the T and B cells of jawed vertebrates, but they express variable lymphocyte receptors (VLRs) instead of the T and B cell receptors that specifically recognize antigens in jawed vertebrates. These VLRs act as antigen receptors, diversity being generated in their antigen-binding sites by assembly of highly diverse leucine-rich repeat modules. Therefore, jawless vertebrates have developed adaptive immune systems based on the VLRs. Although pattern recognition receptors, including Toll-like receptors (TLRs) and Rig-like receptors (RLRs), and their adaptor genes are conserved in jawless vertebrates, some transcription factor and inflammatory cytokine genes in the TLR and RLR pathways are not present. However, like jawed vertebrates, the initiation of adaptive immune responses in jawless vertebrates appears to require prior activation of the innate immune system. These observations imply that the innate immune systems of jawless vertebrates have a unique molecular basis that is distinct from that of jawed vertebrates. Altogether, although the molecular details of the innate and adaptive immune systems differ between jawless and jawed vertebrates, jawless vertebrates have developed versions of these immune systems that are similar to those of jawed vertebrates.

  8. Alzheimer's disease: Innate immunity gone awry?

    PubMed

    VanItallie, Theodore B

    2017-01-11

    Inflammation is an immune activity designed to protect the host from pathogens and noxious agents. In its low-intensity form, presence of an inflammatory process must be inferred from appropriate biomarkers. Occult neuroinflammation is not just secondary to Alzheimer's disease (AD) but may contribute to its pathogenesis and promote its progression. A leaky blood-brain barrier (BBB) has been observed in early AD and may play a role in its initiation and development. Studies of the temporal evolution of AD's biomarkers have shown that, in AD, the brain's amyloid burden correlates poorly with cognitive decline. In contrast, cognitive deficits in AD correlate well with synapse loss. Oligomeric forms of amyloid-beta (oAβs) can be synaptotoxic and evidence of their deposition inside synaptic terminals of cognition-associated neurons explains early memory loss in AD better than formation of extracellular Aβ plaques. Among innate immune cells that reside in the brain, microglia sense danger signals represented by proteins like oAβ and become activated by neuronal damage such as that caused by bacterial endotoxins. The resulting reactive microgliosis has been implicated in generating the chronic form of microglial activation believed to promote AD's development. Genome-wide association studies (GWASs) have yielded data from patients with sporadic AD indicating that its causes include genetic variation in the innate immune system. Recent preclinical studies have reported that β-hydroxybutyrate (βOHB) may protect the brain from the adverse effects of both the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome and the deacetylation of histone. Consequently, there is an urgent need for clinical investigations designed to test whether an orally administered βOHB preparation, such as a ketone ester, can have a similar beneficial effect in human subjects.

  9. Antimicrobial Peptides as Mediators of Innate Immunity in Teleosts

    PubMed Central

    Katzenback, Barbara A.

    2015-01-01

    Antimicrobial peptides (AMPs) have been identified throughout the metazoa suggesting their evolutionarily conserved nature and their presence in teleosts is no exception. AMPs are short (18–46 amino acids), usually cationic, amphipathic peptides. While AMPs are diverse in amino acid sequence, with no two AMPs being identical, they collectively appear to have conserved functions in the innate immunity of animals towards the pathogens they encounter in their environment. Fish AMPs are upregulated in response to pathogens and appear to have direct broad-spectrum antimicrobial activity towards both human and fish pathogens. However, an emerging role for AMPs as immunomodulatory molecules has become apparent—the ability of AMPs to activate the innate immune system sheds light onto the multifaceted capacity of these small peptides to combat pathogens through direct and indirect means. Herein, this review focuses on the role of teleost AMPs as modulators of the innate immune system and their regulation in response to pathogens or other exogenous molecules. The capacity to regulate AMP expression by exogenous factors may prove useful in modulating AMP expression in fish to prevent disease, particularly in aquaculture settings where crowded conditions and environmental stress pre-dispose these fish to infection. PMID:26426065

  10. Tuning innate immunity by translation.

    PubMed

    Rauscher, Robert; Ignatova, Zoya

    2015-12-01

    In multicellular organisms, the epithelia is a contact surface with the surrounding environment and is exposed to a variety of adverse biotic (pathogenic) and abiotic (chemical) factors. Multi-layered pathways that operate on different time scales have evolved to preserve cellular integrity and elicit stress-specific response. Several stress-response programs are activated until a complete elimination of the stress is achieved. The innate immune response, which is triggered by pathogenic invasion, is rather harmful when active over a prolonged time, thus the response follows characteristic oscillatory trajectories. Here, we review different translation programs that function to precisely fine-tune the time at which various components of the innate immune response dwell between active and inactive. We discuss how different pro-inflammatory pathways are co-ordinated to temporally offset single reactions and to achieve an optimal balance between fighting pathogens and being less harmful for healthy cells.

  11. Taste Receptors in Innate Immunity

    PubMed Central

    Lee, Robert J.

    2014-01-01

    Taste receptors were first identified on the tongue, where they initiate a signaling pathway that communicates information to the brain about the nutrient content or potential toxicity of ingested foods. However, recent research has shown that taste receptors are also expressed in a myriad of other tissues, from the airway and gastrointestinal epithelia to the pancreas and brain. The functions of many of these extraoral taste receptors remain unknown, but emerging evidence suggests that bitter and sweet taste receptors in the airway are important sentinels of innate immunity. This review discusses taste receptor signaling, focusing on the G-protein coupled–receptors that detect bitter, sweet, and savory tastes, followed by an overview of extraoral taste receptors and in-depth discussion of studies demonstrating the roles of taste receptors in airway innate immunity. Future research on extraoral taste receptors has significant potential for identification of novel immune mechanisms and insights into host-pathogen interactions. PMID:25323130

  12. Developmental programming of natural killer and innate lymphoid cells.

    PubMed

    Vosshenrich, Christian A J; Di Santo, James P

    2013-04-01

    In recent years we have witnessed a blooming interest in innate lymphoid cell (ILC) biology thanks to the discovery of novel lineages of ILC that are phenotypically and functionally distinct from NK cells. While the importance of these novel ILC subsets as essential functional components of the early immune responses are now clearly established, many questions remain as to how early ILC developmental fates are determined and how specific effector functions associated with individual ILC subsets are achieved. As the founding member of the ILC family, properties of NK cells have defining attributes that characterize this group of innate effectors. Analysing their developmental rules may provide clues to principles that guide ILC development in general.

  13. Clinical improvement and radiological progression in a girl with early onset scoliosis (EOS) treated conservatively – a case report

    PubMed Central

    Weiss, Hans-Rudolf

    2006-01-01

    Background Chêneau-Brace treatment of a certain standard reduces the rate of surgery, prevents progression and in a certain patient population leads to marked improvement of Cobb angle and cosmetic appearance. During the last two years a patient refusing surgery with a double major curvature of initially 60° showed a clear cosmetic improvement and a clear radiological progression at the same time. The findings of this patient have been reviewed in order to find out how cosmetic appearance and Cobb angle can develop differently. Methods The patient entered conservative treatment at the age of 13 years, premenarchial with Tanner II and a Cobb angle of 60° thoracic and 59° lumbar. The angle of trunk rotation (ATR; Scoliometer) was 13° thoracic and 13° lumbar. We have documented the findings of this patient (Surface topography, ATR, Cobb angles and angles of vertebral rotation (according to Raimondi) during the treatment period (27 Month) until 2 years after the onset of menarche. Results After a treatment time of 27 Month the Cobb angle increased to 74° thoracic and 65° lumbar. The angles of vertebral rotation according to Raimondi increased slightly from 26° thoracic and 28° lumbar to 30° thoracic and 28° lumbar. The ATR improved to 12° thoracic and 5° lumbar while Lateral deviation improved from 22,4 mm to 4,6 mm and average surface rotation improved from 10,6° to 6°. In the X-rays a reduction of decompensation was visible. The patient felt comfortable with the cosmetic result. Conclusion Conservative treatment may improve cosmetic appearance while the curve progresses radiologically. This could be explained by assuming that (1) the Rigo Chêneau brace is able to improve cosmetic appearance by changing the shape of the thorax when the curve itself is too stiff to be corrected by a brace, that (2) reduction of decompensation leads to significant cosmetical improvements or (3) that the patient gained weight and therefore the deformation is masked

  14. How a low tissue O2 strategy could be conserved in early crustaceans: the example of the podocopid ostracods.

    PubMed

    Corbari, Laure; Carbonel, Pierre; Massabuau, Jean-Charles

    2004-12-01

    An adaptation strategy whereby O(2) partial pressure, P(O(2)), in the tissues is maintained within a low, narrow range of 1-3 kPa, largely independent of the inspired P(O(2)), has been reported in water- and air-breathing poikilotherms and in homeotherms. Based on the postulate that this basic cellular mechanism has been established since the early stages of evolution, it has been hypothesized that it could be the consequence of an early adaptation strategy to maintain cellular oxygenation within the same low and primitive range. To test this hypothesis we studied the basic mechanisms of oxygen regulation in podocopid ostracods, minute crustaceans that have existed on earth for at least 500 million years. Podocopids lack any regulatory mechanism for adapting their ventilation to cope with changes in water oxygenation, and instead adjust their tissue oxygenation status by migrating through the O(2) gradient to sediment layers where the P(O(2)) of the water is 3-5 kPa. Experimental manipulation of the O(2) profile induced their vertical migration to follow this precise water P(O(2)) and demonstrates the existence of a regulation strategy. This strategy must be associated with the lower P(O(2)) values within the animal's carapace valves, showing that podocopids can actively regulate their tissue P(O(2)) at constant but even lower values than the water. In conclusion, the low tissue P(O(2)) strategy could have existed in early crustaceans and, by extension, in early animals.

  15. Innate Immune Responses and Chronic Obstructive Pulmonary Disease

    PubMed Central

    Schleimer, Robert P.

    2005-01-01

    Innate immune responses appear to be partially responsible for maintaining inflammation and tissue destruction in chronic obstructive pulmonary disease. In the early stages of the disease in smokers, the airways are bombarded with large quantities of particulate material, and activation of phagocytic cells results in the release of many of the mediators believed to remodel the airways. Ironically, failure of the innate immune defense system, either by inherited deficiency or as a result of chronic smoke inhalation, is likely to result in increased susceptibility to infectious disease and exacerbations of chronic obstructive pulmonary disease. It is well known that deficiencies in the production of collectins, pentraxins, and complement can lead to increased infections, and several studies indicate that deficiency in one or another innate defense component is associated with increased exacerbations. Corticosteroids reduce exacerbations in part because of their ability to boost the production of innate host-defense molecules. Therapeutic approaches that stimulate the generation of antimicrobial molecules in the lungs might be able to reduce disease exacerbations. PMID:16267360

  16. The Innate Immune System in Acute and Chronic Wounds

    PubMed Central

    MacLeod, Amanda S.; Mansbridge, Jonathan N.

    2016-01-01

    Significance: This review article provides an overview of the critical roles of the innate immune system to wound healing. It explores aspects of dysregulation of individual innate immune elements known to compromise wound repair and promote nonhealing wounds. Understanding the key mechanisms whereby wound healing fails will provide seed concepts for the development of new therapeutic approaches. Recent Advances: Our understanding of the complex interactions of the innate immune system in wound healing has significantly improved, particularly in our understanding of the role of antimicrobials and peptides and the nature of the switch from inflammatory to reparative processes. This takes place against an emerging understanding of the relationship between human cells and commensal bacteria in the skin. Critical Issues: It is well established and accepted that early local inflammatory mediators in the wound bed function as an immunological vehicle to facilitate immune cell infiltration and microbial clearance upon injury to the skin barrier. Both impaired and excessive innate immune responses can promote nonhealing wounds. It appears that the switch from the inflammatory to the proliferative phase is tightly regulated and mediated, at least in part, by a change in macrophages. Defining the factors that initiate the switch in such macrophage phenotypes and functions is the subject of multiple investigations. Future Directions: The review highlights processes that may be useful targets for further investigation, particularly the switch from M1 to M2 macrophages that appears to be critical as dysregulation of this switch occurs during defective wound healing. PMID:26862464

  17. Early changes in bone density, microarchitecture, bone resorption, and inflammation predict the clinical outcome 12 weeks after conservatively treated distal radius fractures: an exploratory study.

    PubMed

    Meyer, Ursina; de Jong, Joost J; Bours, Sandrine G P; Keszei, András P; Arts, Jacobus J; Brink, Peter R G; Menheere, Paul; van Geel, Tineke A C M; van Rietbergen, Bert; van den Bergh, Joop P W; Geusens, Piet P; Willems, Paul C

    2014-09-01

    Fracture healing is an active process with early changes in bone and inflammation. We performed an exploratory study evaluating the association between early changes in densitometric, structural, biomechanical, and biochemical bone parameters during the first weeks of fracture healing and wrist-specific pain and disability at 12 weeks in postmenopausal women with a conservatively treated distal radius fracture. Eighteen patients (aged 64 ± 8 years) were evaluated at 1 to 2 and 3 to 4 weeks postfracture, using high-resolution peripheral quantitative computed tomography (HR-pQCT), micro-finite element analysis, serum procollagen type-I N-terminal propeptide (P1NP), carboxy-terminal telopeptide of type I collagen (ICTP), and high-sensitive C-reactive protein (hsCRP). After 12 weeks, patients rated their pain and disability using Patient Rated Wrist Evaluation (PRWE) questionnaire. Additionally, Quick Disability of the Arm Shoulder and Hand (QuickDASH) questionnaire and active wrist range of motion was evaluated. Linear regression models were used to study the relationship between changes in bone parameters and in hsCRP from visit 1 to 2 and PRWE score after 12 weeks. A lower PRWE outcome, indicating better outcome, was significantly related to an early increase in trabecular bone mineral density (BMD) (β -0.96 [95% CI -1.75 to -0.16], R(2)  = 0.37), in torsional stiffness (-0.14 [-0.28 to -0.004], R(2)  = 0.31), and to an early decrease in trabecular separation (209 [15 to 402], R(2)  = 0.33) and in ICTP (12.1 [0.0 to 24.1], R(2)  = 0.34). Similar results were found for QuickDASH. Higher total dorsal and palmar flexion range of motion was significantly related to early increase in hsCRP (9.62 [3.90 to 15.34], R(2)  = 0.52). This exploratory study indicates that the assessment of early changes in trabecular BMD, trabecular separation, calculated torsional stiffness, bone resorption marker ICTP, and hsCRP after a distal radius fracture provides

  18. Nonclassical MHC class I-dependent invariant T cells are evolutionarily conserved and prominent from early development in amphibians.

    PubMed

    Edholm, Eva-Stina; Albertorio Saez, Liz-Marie; Gill, Ann L; Gill, Steven R; Grayfer, Leon; Haynes, Nikesha; Myers, Jason R; Robert, Jacques

    2013-08-27

    Human and murine MHC nonclassical class Ib-restricted invariant T (iT) cell subsets, such as invariant natural killer T cells (iNKT) and mucosal-associated invariant T cells, have specialized functions early in immune responses, especially in modulating subsequent adaptive immune responses. Here, we characterize a prominent iT population in the amphibian Xenopus laevis and show the requirement of the class Ib molecule, Xenopus nonclassical gene 10, in its differentiation and function. Using Xenopus nonclassical gene 10 tetramers and RNAi loss of function by transgenesis, we identified a large class Ib-dependent CD8(-)/CD4(-) iT subset in unmanipulated frogs and tadpoles. This population is critical for antiviral immunity during early larval stages when classical MHC class Ia function is suboptimal. Furthermore, in young tadpoles with low class Ia expression, deep sequencing revealed additional preponderant invariant T cell receptor (TCR)α rearrangements, implying other iT cell subsets and a predominant selection process mediated by other class Ib molecules. The restriction and requirement of class Ib molecules for development and antiviral immunity of a mammalian iNKT or mucosal-associated invariant T cell counterpart in the amphibian Xenopus show the importance of iT cells in the emergence and evolution of the adaptive immune system.

  19. Highly conserved functions of the Brachyury gene on morphogenetic movements: insight from the early-diverging phylum Ctenophora.

    PubMed

    Yamada, Atsuko; Martindale, Mark Q; Fukui, Akimasa; Tochinai, Shin

    2010-03-01

    Brachyury, a member of the T-box transcription family identified in a diverse array of metazoans, was initially recognized for its function in mesoderm formation and notochord differentiation in vertebrates; however, its ancestral role has been suggested to be in control of morphogenetic movements. Here, we show that morpholino oligonucleotide knockdown of Brachyury (MlBra) in embryos of a ctenophore, one of the most ancient groups of animals, prevents the invagination of MlBra expressing stomodeal cells and is rescued with corresponding RNA injections. Injection of RNA encoding a dominant-interfering construct of MlBra causes identical phenotypes to that of RNA encoding a dominant-interfering form of Xenopus Brachyury (Xbra) in Xenopus embryos. Both injected embryos down-regulate Xbra downstream genes, Xbra itself and Xwnt11 but not axial mesodermal markers, resulting in failure to complete gastrulation due to loss of convergent extension movements. Moreover, animal cap assay reveals that MlBra induces Xwnt11 like Xbra. Overall results using Xenopus embryos show that these two genes are functionally interchangeable. These functional experiments demonstrate for the first time in a basal metazoan that the primitive role of Brachyury is to regulate morphogenetic movements, rather than to specify endomesodermal fates, and the role is conserved between non-bilaterian metazoans and vertebrates.

  20. Two Centuries of Soil Conservation.

    ERIC Educational Resources Information Center

    Helms, Douglas

    1991-01-01

    Narrates U.S. soil conservation history since the late eighteenth century. Discusses early practices such as contour plowing. Profiles individuals who promoted soil conservation and were largely responsible for the creation of the Soil Conservation Service. Explains the causes of erosion and how soil conservation districts help farmers prevent…

  1. The birth of innate immunity.

    PubMed

    Gallo, Richard L

    2013-08-01

    Modern immunology has seen an apparent revolution with the recognition that human immune defense is not only the responsibility of bone marrow-derived leucocytes, but also dependent on a coordinated network of many cell types including epithelial cells, fibroblasts and neural elements. This classic paper by Alexander Fleming and V.D. Allison (British J of Exp Path, 111, 1922, 252) was largely forgotten for 75 years and describes the discovery that epithelia produce a protein with direct antimicrobial activity. Thus, this paper represents the birth of the field now referred to as innate immunity and first describes an antimicrobial protein (AMP).

  2. The conservative behavior of dissolved organic carbon in surface waters of the southern Chukchi Sea, Arctic Ocean, during early summer

    PubMed Central

    Tanaka, Kazuki; Takesue, Nobuyuki; Nishioka, Jun; Kondo, Yoshiko; Ooki, Atsushi; Kuma, Kenshi; Hirawake, Toru; Yamashita, Youhei

    2016-01-01

    The spatial distribution of dissolved organic carbon (DOC) concentrations and the optical properties of dissolved organic matter (DOM) determined by ultraviolet-visible absorbance and fluorescence spectroscopy were measured in surface waters of the southern Chukchi Sea, western Arctic Ocean, during the early summer of 2013. Neither the DOC concentration nor the optical parameters of the DOM correlated with salinity. Principal component analysis using the DOM optical parameters clearly separated the DOM sources. A significant linear relationship was evident between the DOC and the principal component score for specific water masses, indicating that a high DOC level was related to a terrigenous source, whereas a low DOC level was related to a marine source. Relationships between the DOC and the principal component scores of the surface waters of the southern Chukchi Sea implied that the major factor controlling the distribution of DOC concentrations was the mixing of plural water masses rather than local production and degradation. PMID:27658444

  3. The conservative behavior of dissolved organic carbon in surface waters of the southern Chukchi Sea, Arctic Ocean, during early summer.

    PubMed

    Tanaka, Kazuki; Takesue, Nobuyuki; Nishioka, Jun; Kondo, Yoshiko; Ooki, Atsushi; Kuma, Kenshi; Hirawake, Toru; Yamashita, Youhei

    2016-09-23

    The spatial distribution of dissolved organic carbon (DOC) concentrations and the optical properties of dissolved organic matter (DOM) determined by ultraviolet-visible absorbance and fluorescence spectroscopy were measured in surface waters of the southern Chukchi Sea, western Arctic Ocean, during the early summer of 2013. Neither the DOC concentration nor the optical parameters of the DOM correlated with salinity. Principal component analysis using the DOM optical parameters clearly separated the DOM sources. A significant linear relationship was evident between the DOC and the principal component score for specific water masses, indicating that a high DOC level was related to a terrigenous source, whereas a low DOC level was related to a marine source. Relationships between the DOC and the principal component scores of the surface waters of the southern Chukchi Sea implied that the major factor controlling the distribution of DOC concentrations was the mixing of plural water masses rather than local production and degradation.

  4. Profile of prognostic factors in 1022 Indian women with early-stage breast cancer treated with breast-conserving therapy

    SciTech Connect

    Dinshaw, Ketayun A. . E-mail: dinshaw.tmc@vsnl.com; Budrukkar, Ashwini N.; Chinoy, Roshan F.; Sarin, Rajiv; Badwe, Rajendra M.S.; Hawaldar, Rohini; Shrivastava, Shyam Kishore

    2005-11-15

    Purpose: The outcome of breast cancer treatment can vary in different geographic and ethnic groups. A multivariate analysis was performed for various prognostic factors in 1022 Indian women with pathologic Stage I-II breast cancer treated between 1980 and 2000 with standard breast-conserving therapy with or without systemic adjuvant therapy. Methods and Materials: At a mean follow-up of 53 months, the outcomes studied were local failure, locoregional failure, and distant failure, overall survival (OS), and disease-free survival (DFS). Results: The median pathologic tumor size was 3 cm (range, 1-5 cm), and axillary lymph node metastasis was present in 39% of women. The actuarial 5- and 10-year OS and DFS rate was 87% and 77% and 76% and 68%, respectively. Lymphovascular emboli or invasion (LVI) was the strongest independent adverse factor for all failure and survival (local failure, hazard ratio 2.85; 95% confidence interval, 1.68-4.83; OS; hazard ratio, 2.01, 95% confidence interval, 1.35-2.99). Lymph node metastasis was also an independent adverse factor for local failure, locoregional failure, distant failure, DFS, and OS (hazard ratio, 1.55, 95% confidence interval, 1.04-2.30). Age {<=}40 years increased the incidence of local recurrence, and patients with inner quadrant tumors had inferior DFS. The incidence of LVI was significantly greater in women with lymph node metastases than in node-negative women (p < 0.001) and in women with Grade 3 tumors than in those with Grade 1 or 2 tumors (p = 0.001). Conclusion: In Indian women, LVI was the strongest independent prognostic factor for OS, DFS, and local recurrence, irrespective of nodal status and systemic adjuvant treatment. Although LVI may not be a contraindication for BCT, as has been proposed by certain groups, it is necessary to define its role in prospective studies in determining local and systemic treatment.

  5. Innate Immunity Dysregulation in Myelodysplastic Syndromes

    DTIC Science & Technology

    2014-10-01

    proteins linking innate and acquired 22 immunity. Nature immunology 2001; 2(8): 675-680. 23 24 57. Li J, Wang X, Zhang F, Yin H. Toll-like receptors...AD_________________ Award Number: W81XWH-12-1-0221 TITLE: Innate Immunity Dysregulation in...30 Sept 2013 – 29 Sept 2014 4. TITLE AND SUBTITLE “ Innate Immunity Dysregulation in Myelodysplastic Syndromes” 5a. CONTRACT NUMBER 5b

  6. The biology of innate lymphoid cells.

    PubMed

    Artis, David; Spits, Hergen

    2015-01-15

    The innate immune system is composed of a diverse array of evolutionarily ancient haematopoietic cell types, including dendritic cells, monocytes, macrophages and granulocytes. These cell populations collaborate with each other, with the adaptive immune system and with non-haematopoietic cells to promote immunity, inflammation and tissue repair. Innate lymphoid cells are the most recently identified constituents of the innate immune system and have been the focus of intense investigation over the past five years. We summarize the studies that formally identified innate lymphoid cells and highlight their emerging roles in controlling tissue homeostasis in the context of infection, chronic inflammation, metabolic disease and cancer.

  7. Time Interval From Breast-Conserving Surgery to Breast Irradiation in Early Stage Node-Negative Breast Cancer: 17-Year Follow-Up Results and Patterns of Recurrence

    SciTech Connect

    Vujovic, Olga; Yu, Edward; Cherian, Anil; Dar, A. Rashid; Stitt, Larry; Perera, Francisco

    2015-02-01

    Purpose: A retrospectivechart review was conducted to determine whether the time interval from breast-conserving surgery to breast irradiation (surgery-radiation therapy interval) in early stage node-negative breast cancer had any detrimental effects on recurrence rates. Methods and Materials: There were 566 patients with T1 to T3, N0 breast cancer treated with breast-conserving surgery and breast irradiation and without adjuvant systemic treatment between 1985 and 1992. The surgery-to-radiation therapy intervals used for analysis were 0 to 8 weeks (201 patients), >8 to 12 weeks (233 patients), >12 to 16 weeks (91 patients), and >16 weeks (41 patients). Kaplan-Meier estimates of time to local recurrence, disease-free survival, distant disease-free survival, cause-specific survival, and overall survival rates were calculated. Results: Median follow-up was 17.4 years. Patients in all 4 time intervals were similar in terms of characteristics and pathologic features. There were no statistically significant differences among the 4 time groups in local recurrence (P=.67) or disease-free survival (P=.82). The local recurrence rates at 5, 10, and 15 years were 4.9%, 11.5%, and 15.0%, respectively. The distant disease relapse rates at 5, 10, and 15 years were 10.6%, 15.4%, and 18.5%, respectively. The disease-free failure rates at 5, 10, and 15 years were 20%, 32.3%, and 39.8%, respectively. Cause-specific survival rates at 5, 10, and 15 years were 92%, 84.6%, and 79.8%, respectively. The overall survival rates at 5, 10, and 15 years were 89.3%, 79.2%, and 66.9%, respectively. Conclusions: Surgery-radiation therapy intervals up to 16 weeks from breast-conserving surgery are not associated with any increased risk of recurrence in early stage node-negative breast cancer. There is a steady local recurrence rate of 1% per year with adjuvant radiation alone.

  8. Evolutionarily Conserved Function of RRP36 in Early Cleavages of the Pre-rRNA and Production of the 40S Ribosomal Subunit ▿ †

    PubMed Central

    Gérus, Marie; Bonnart, Chrystelle; Caizergues-Ferrer, Michèle; Henry, Yves; Henras, Anthony K.

    2010-01-01

    Ribosome biogenesis in eukaryotes is a major cellular activity mobilizing the products of over 200 transcriptionally coregulated genes referred to as the rRNA and ribosome biosynthesis regulon. We investigated the function of an essential, uncharacterized gene of this regulon, renamed RRP36. We show that the Rrp36p protein is nucleolar and interacts with 90S and pre-40S preribosomal particles. Its depletion affects early cleavages of the 35S pre-rRNA and results in a rapid decrease in mature 18S rRNA levels. Rrp36p is a novel component of the 90S preribosome, the assembly of which has been suggested to result from the stepwise incorporation of several modules, including the tUTP/UTP-A, PWP2/UTP-B, and UTP-C subcomplexes. We show that Rrp36p depletion does not impair the incorporation of these subcomplexes and the U3 small nucleolar RNP into preribosomes. In contrast, depletion of components of the UTP-A or UTP-B modules, but not Rrp5p, prevents Rrp36p recruitment and reduces its accumulation levels. In parallel, we studied the human orthologue of Rrp36p in HeLa cells, and we show that the function of this protein in early cleavages of the pre-rRNA has been conserved through evolution in eukaryotes. PMID:20038530

  9. Conservation of Male Sterility 2 function during spore and pollen wall development supports an evolutionarily early recruitment of a core component in the sporopollenin biosynthetic pathway.

    PubMed

    Wallace, Simon; Chater, Caspar C; Kamisugi, Yasuko; Cuming, Andrew C; Wellman, Charles H; Beerling, David J; Fleming, Andrew J

    2015-01-01

    The early evolution of plants required the acquisition of a number of key adaptations to overcome physiological difficulties associated with survival on land. One of these was a tough sporopollenin wall that enclosed reproductive propagules and provided protection from desiccation and UV-B radiation. All land plants possess such walled spores (or their derived homologue, pollen). We took a reverse genetics approach, consisting of knock-out and complementation experiments to test the functional conservation of the sporopollenin-associated gene MALE STERILTY 2 (which is essential for pollen wall development in Arabidopsis thaliana) in the bryophyte Physcomitrella patens. Knock-outs of a putative moss homologue of the A. thaliana MS2 gene, which is highly expressed in the moss sporophyte, led to spores with highly defective walls comparable to that observed in the A. thaliana ms2 mutant, and extremely compromised germination. Conversely, the moss MS2 gene could not rescue the A. thaliana ms2 phenotype. The results presented here suggest that a core component of the biochemical and developmental pathway required for angiosperm pollen wall development was recruited early in land plant evolution but the continued increase in pollen wall complexity observed in angiosperms has been accompanied by divergence in MS2 gene function.

  10. Ultra-deep sequencing of ribosome-associated poly-adenylated RNA in early Drosophila embryos reveals hundreds of conserved translated sORFs.

    PubMed

    Li, Hongmei; Hu, Chuansheng; Bai, Ling; Li, Hua; Li, Mingfa; Zhao, Xiaodong; Czajkowsky, Daniel M; Shao, Zhifeng

    2016-12-01

    There is growing recognition that small open reading frames (sORFs) encoding peptides shorter than 100 amino acids are an important class of functional elements in the eukaryotic genome, with several already identified to play critical roles in growth, development, and disease. However, our understanding of their biological importance has been hindered owing to the significant technical challenges limiting their annotation. Here we combined ultra-deep sequencing of ribosome-associated poly-adenylated RNAs with rigorous conservation analysis to identify a comprehensive population of translated sORFs during early Drosophila embryogenesis. In total, we identify 399 sORFs, including those previously annotated but without evidence of translational capacity, those found within transcripts previously classified as non-coding, and those not previously known to be transcribed. Further, we find, for the first time, evidence for translation of many sORFs with different isoforms, suggesting their regulation is as complex as longer ORFs. Furthermore, many sORFs are found not associated with ribosomes in late-stage Drosophila S2 cells, suggesting that many of the translated sORFs may have stage-specific functions during embryogenesis. These results thus provide the first comprehensive annotation of the sORFs present during early Drosophila embryogenesis, a necessary basis for a detailed delineation of their function in embryogenesis and other biological processes.

  11. A glimpse into the early origins of medieval anatomy through the oldest conserved human dissection (Western Europe, 13th c. A.D.)

    PubMed Central

    Huynh-Charlier, Isabelle; Poupon, Joël; Lancelot, Eloïse; Campos, Paula F.; Favier, Dominique; Jeannel, Gaël-François; Bonati, Maurizio Rippa; de la Grandmaison, Geoffroy Lorin; Hervé, Christian

    2013-01-01

    Introduction Medieval autopsy practice is very poorly known in Western Europe, due to a lack of both descriptive medico-surgical texts and conserved dissected human remains. This period is currently considered the dark ages according to a common belief of systematic opposition of Christian religious authorities to the opening of human cadavers. Material and methods The identification in a private collection of an autopsied human individual dated from the 13th century A.D. is an opportunity for better knowledge of such practice in this chrono-cultural context, i.e. the early origins of occidental dissections. A complete forensic anthropological procedure was carried out, completed by radiological and elemental analyses. Results The complete procedure of this body opening and internal organs exploration is explained, and compared with historical data about forensic and anatomical autopsies from this period. During the analysis, a red substance filling all arterial cavities, made of mercury sulfide (cinnabar) mixed with vegetal oil (oleic and palmitic acids) was identified; it was presumably used to highlight vascularization by coloring in red such vessels, and help in the preservation of the body. Conclusions Of particular interest for the description of early medical and anatomical knowledge, this “human preparation” is the oldest known yet, and is particularly important for the fields of history of medicine, surgery and anatomical practice. PMID:24904674

  12. Toward understanding of rice innate immunity against Magnaporthe oryzae.

    PubMed

    Azizi, P; Rafii, M Y; Abdullah, S N A; Nejat, N; Maziah, M; Hanafi, M M; Latif, M A; Sahebi, M

    2016-01-01

    The blast fungus, Magnaporthe oryzae, causes serious disease on a wide variety of grasses including rice, wheat and barley. The recognition of pathogens is an amazing ability of plants including strategies for displacing virulence effectors through the adaption of both conserved and variable pathogen elicitors. The pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) and effector-triggered immunity (ETI) were reported as two main innate immune responses in plants, where PTI gives basal resistance and ETI confers durable resistance. The PTI consists of extracellular surface receptors that are able to recognize PAMPs. PAMPs detect microbial features such as fungal chitin that complete a vital function during the organism's life. In contrast, ETI is mediated by intracellular receptor molecules containing nucleotide-binding (NB) and leucine rich repeat (LRR) domains that specifically recognize effector proteins produced by the pathogen. To enhance crop resistance, understanding the host resistance mechanisms against pathogen infection strategies and having a deeper knowledge of innate immunity system are essential. This review summarizes the recent advances on the molecular mechanism of innate immunity systems of rice against M. oryzae. The discussion will be centered on the latest success reported in plant-pathogen interactions and integrated defense responses in rice.

  13. Meeting the demand for innate and adaptive immunities during evolution.

    PubMed

    Du Pasquier, L

    2005-07-01

    An ideal immune system should provide each individual with rapid and efficient responses, a diverse repertoire of recognition and effector molecules and a certain flexibility to match the changing internal and external environment. It should be economic in cells and genes. Specific memory would be useful. It should not be autoreactive. These requirements, a mixture of innate and adaptive immunity features, are modulated in function of the dominant mode of selection for each species of metazoa during evolution (K or r). From sponges to man, a great diversity of receptors and effector mechanisms, some of them shared with plants, are articulated around conserved signalling cascades. Multiple attempts at combining innate and adaptive immunity somatic features can be observed as new somatic mechanisms provide individualized repertoires of receptors throughout metazoa, in agnathans, prochordates, echinoderms and mollusks. The adaptive immunity of vertebrates with lymphocytes and their specific receptors of the immunoglobulin superfamily, the major histocompatibility complex, developed from innate immunity evolutionary lines that can be traced back in earlier deuterostomes.

  14. Identification and Validation of Ifit1 as an Important Innate Immune Bottleneck

    SciTech Connect

    McDermott, Jason E.; Vartanian, Keri B.; Mitchell, Hugh D.; Stevens, S.L.; Sanfilippo, Antonio P.; Stenzel-Poore, Mary

    2012-06-20

    The innate immune system plays important roles in a number of disparate processes. Foremost, innate immunity is a first responder to invasion by pathogens and triggers early defensive responses and recruits the adaptive immune system. The innate immune system also responds to endogenous damage signals that arise from tissue injury. Recently it has been found that innate immunity plays an important role in neuroprotection against ischemic stroke through the activation of the primary innate immune receptors, Toll-like receptors (TLRs). Using several large-scale transcriptomic data sets from mouse and mouse macrophage studies we identified targets predicted to be important in controlling innate immune processes initiated by TLR activation. Targets were identified as genes with high betweenness centrality, so-called bottlenecks, in networks inferred from statistical associations between gene expression patterns. A small set of putative bottlenecks were identified in each of the data sets investigated including interferon-stimulated genes (Ifit1, Ifi47, Tgtp and Oasl2) as well as genes uncharacterized in immune responses (Axud1 and Ppp1r15a). We further validated one of these targets, Ifit1, in mouse macrophages by showing that silencing it suppresses induction of predicted downstream genes by lipopolysaccharide (LPS)-mediated TLR4 activation through an unknown direct or indirect mechanism. Our study demonstrates the utility of network analysis for identification of interesting targets related to innate immune function, and highlights that Ifit1 can exert a positive regulatory effect on downstream genes.

  15. Beyond NK cells: the expanding universe of innate lymphoid cells.

    PubMed

    Cella, Marina; Miller, Hannah; Song, Christina

    2014-01-01

    For a long time, natural killer (NK) cells were thought to be the only innate immune lymphoid population capable of responding to invading pathogens under the influence of changing environmental cues. In the last few years, an increasing amount of evidence has shown that a number of different innate lymphoid cell (ILC) populations found at mucosal sites rapidly respond to locally produced cytokines in order to establish or maintain homeostasis. These ILC populations closely mirror the phenotype of adaptive T helper subsets in their repertoire of secreted soluble factors. Early in the immune response, ILCs are responsible for setting the stage to mount an adaptive T cell response that is appropriate for the incoming insult. Here, we review the diversity of ILC subsets and discuss similarities and differences between ILCs and NK cells in function and key transcriptional factors required for their development.

  16. Strength in numbers: "Omics" studies of C. elegans innate immunity.

    PubMed

    Simonsen, Karina T; Gallego, Sandra F; Færgeman, Nils J; Kallipolitis, Birgitte H

    2012-10-01

    For more than ten years the nematode Caenorhabditis elegans has proven to be a valuable model for studies of the host response to various bacterial and fungal pathogens. When exposed to a pathogenic organism, a clear response is elicited in the nematode, which is characterized by specific alterations on the transcriptional and translational levels. Early on, researchers took advantage of the possibility to conduct large-scale investigations of the C. elegans immune response. Multiple studies demonstrated that C. elegans does indeed mount a protective response against invading pathogens, thus rendering this small nematode a very useful and simple host model for the study of innate immunity and host-pathogen interactions. Here, we provide an overview of key aspects of innate immunity in C. elegans revealed by recent whole-genome transcriptomics and proteomics studies of the global response of C. elegans to various bacterial and fungal pathogens.

  17. Evaluation of Vascular Endothelial Growth Factor as a Prognostic Marker for Local Relapse in Early-Stage Breast Cancer Patients Treated With Breast-Conserving Therapy

    SciTech Connect

    Moran, Meena S.; Yang Qifeng; Goyal, Sharad; Harris, Lyndsay; Chung, Gina; Haffty, Bruce G.

    2011-12-01

    Purpose: Vascular endothelial growth factor (VEGF) is an important protein involved in the process of angiogenesis that has been found to correlate with relapse-free and overall survival in breast cancer, predominantly in locally advanced and metastatic disease. A paucity of data is available on the prognostic implications of VEGF in early-stage breast cancer; specifically, its prognostic value for local relapse after breast-conserving therapy (BCT) is largely unknown. The purpose of our study was to assess VEGF expression in a cohort of early-stage breast cancer patients treated with BCT and to correlate the clinical and pathologic features and outcomes with overexpression of VEGF. Methods and Materials: After obtaining institutional review board approval, the paraffin specimens of 368 patients with early-stage breast cancer treated with BCT between 1975 and 2005 were constructed into tissue microarrays with twofold redundancy. The tissue microarrays were stained for VEGF and read by a trained pathologist, who was unaware of the clinical details, as positive or negative according the standard guidelines. The clinical and pathologic data, long-term outcomes, and results of VEGF staining were analyzed. Results: The median follow-up for the entire cohort was 6.5 years. VEGF expression was positive in 56 (15%) of the 368 patients. Although VEGF expression did not correlate with age at diagnosis, tumor size, nodal status, histologic type, family history, estrogen receptor/progesterone receptor status, or HER-2 status, a trend was seen toward increased VEGF expression in the black cohort (26% black vs. 13% white, p = .068). Within the margin-negative cohort, VEGF did not predict for local relapse-free survival (RFS) (96% vs. 95%), nodal RFS (100% vs. 100%), distant metastasis-free survival (91% vs. 92%), overall survival (92% vs. 97%), respectively (all p >.05). Subset analysis revealed that VEGF was highly predictive of local RFS in node-positive, margin

  18. [Innate immunity, Toll receptor and sepsis].

    PubMed

    Carrillo-Esper, Raúl

    2003-01-01

    The innate immune response is the first line of defense against infection. Toll-like receptors (TLRs) recognize bacterial lipopolysaccharide and other pathogen-associated molecular patterns (PAMPs). Intracellular signals initiated by interaction between Toll receptors and specific PAMPs results in inflammatory response. Sepsis and septic shock are the result of an exaggerated inflammatory systemic response induced by innate immune dysregulation.

  19. The innate immune response to hepatitis B virus infection: implications for pathogenesis and therapy.

    PubMed

    Chang, Jinhong; Block, Timothy M; Guo, Ju-Tao

    2012-12-01

    Pattern recognition receptor (PRR)-mediated innate immune responses play an essential role in defending the host from viral infections. Intriguingly, hepatitis B virus (HBV) has been shown to induce negligible innate immune responses during the early phase of infection. Whether this is due to the failure of the virus to activate PRRs or suppression of PRR signaling pathways by the virus remains controversial. However, a plethora of evidence suggests that HBV is sensitive to PRR ligand-induced antiviral responses. This review summarizes current understanding of the interaction between HBV and PRR-mediated host innate immunity, antiviral mechanisms of PRR responses against HBV and strategies to combat chronic HBV infection via induction of host innate antiviral responses.

  20. Innate Nuclear Sensor IFI16 Translocates into the Cytoplasm during the Early Stage of In Vitro Human Cytomegalovirus Infection and Is Entrapped in the Egressing Virions during the Late Stage

    PubMed Central

    Dell'Oste, Valentina; Gatti, Deborah; Gugliesi, Francesca; De Andrea, Marco; Bawadekar, Mandar; Lo Cigno, Irene; Biolatti, Matteo; Vallino, Marta; Marschall, Manfred; Gariglio, Marisa

    2014-01-01

    ABSTRACT Intrinsic immune mechanisms mediated by constitutively expressed proteins termed “restriction factors” provide frontline antiviral defense. We recently demonstrated that the DNA sensor IFI16 restricts human cytomegalovirus (HCMV) replication by downregulating viral early and late but not immediate-early mRNAs and their protein expression. We show here that at an early time point during the in vitro infection of low-passage-number human embryonic lung fibroblasts, IFI16 binds to HCMV DNA. However, during a later phase following infection, IFI16 is mislocalized to the cytoplasmic virus assembly complex (AC), where it colocalizes with viral structural proteins. Indeed, upon its binding to pUL97, IFI16 undergoes phosphorylation and relocalizes to the cytoplasm of HCMV-infected cells. ESCRT (endosomal sorting complex required for transport) machinery regulates the translocation of IFI16 into the virus AC by sorting and trafficking IFI16 into multivesicular bodies (MVB), as demonstrated by the interaction of IFI16 with two MVB markers: Vps4 and TGN46. Finally, IFI16 becomes incorporated into the newly assembled virions as demonstrated by Western blotting of purified virions and electron microscopy. Together, these results suggest that HCMV has evolved mechanisms to mislocalize and hijack IFI16, trapping it within mature virions. However, the significance of this IFI16 trapping following nuclear mislocalization remains to be established. IMPORTANCE Intracellular viral DNA sensors and restriction factors are critical components of host defense, which alarm and sensitize immune system against intruding pathogens. We have recently demonstrated that the DNA sensor IFI16 restricts human cytomegalovirus (HCMV) replication by downregulating viral early and late but not immediate-early mRNAs and their protein expression. However, viruses are known to evolve numerous strategies to cope and counteract such restriction factors and neutralize the first line of host

  1. Innate immune receptors in solid organ transplantation.

    PubMed

    Georgel, Philippe

    2016-11-01

    The discovery of Pattern Recognition Receptors (PRRs) followed by that of their role in the early detection of pathogens and the ignition of the innate immune response has been a formidable progress for immunological research in the past 15years. This has massively fueled investigations aiming at developing better strategies to fight off infectious diseases and/or to prevent their occurrence. However, infected individuals are for most part outliers in a given population and therefore, the primary function of these receptors should be considered in pathogen-free conditions. Our current understanding indicates that an important physiological function of PRRs resides in their capacity to maintain epithelial homeostasis in response to colonizing commensals. In addition, endogenous host-derived ligands, expressed under stressed, albeit sterile, conditions (called DAMPs for Danger-Associated Molecular Patterns) are also able to trigger PRR signaling. Solid organ transplantation represents a unique situation where both contributions of PRRs signaling can be studied. Indeed, dysbiosis (either caused by antibiotherapy preceding organ transplantation or simply due to the microbiota differences between the transplanted organ and the recipient host) is a characteristic feature of this situation, which is also marked by a massive synthesis and liberation of DAMPs as a result of hypoxia/reperfusion injury. Therefore, in the transplanted organ, at least two compartments (epithelial and that composed of immune cells) participate in graft rejection/acceptance depending on the activation status of expressed PRRs.

  2. The New Left at California State College, Fullerton: A Case Study of the Radical New Left in a Conservative, State College Community during the 1960s & Early 1970s

    ERIC Educational Resources Information Center

    Thornburg, Barry S.

    2010-01-01

    This dissertation examines the impact and significance of the New Left on the conservative campus and community of California State College, Fullerton (CSF) during the 1960s and early 1970s. Built to meet the demands of the Baby Boom after World War II, CSF became the latest in a series of California State campus expansions in 1959-1960.…

  3. The sequence and antiapoptotic functional domains of the human cytomegalovirus UL37 exon 1 immediate early protein are conserved in multiple primary strains.

    PubMed

    Hayajneh, W A; Colberg-Poley, A M; Skaletskaya, A; Bartle, L M; Lesperance, M M; Contopoulos-Ioannidis, D G; Kedersha, N L; Goldmacher, V S

    2001-01-05

    The human cytomegalovirus UL37 exon 1 gene encodes the immediate early protein pUL37x1 that has antiapoptotic and regulatory activities. Deletion mutagenesis analysis of the open reading frame of UL37x1 identified two domains that are necessary and sufficient for its antiapoptotic activity. These domains are confined within the segments between amino acids 5 to 34, and 118 to 147, respectively. The first domain provides the targeting of the protein to mitochondria. Direct PCR sequencing of UL37 exon 1 amplified from 26 primary strains of human cytomegalovirus demonstrated that the promoter, polyadenylation signal, and the two segments of pUL37x1 required for its antiapoptotic function were invariant in all sequenced strains and identical to those in AD169 pUL37x1. In total, UL37 exon 1 varies between 0.0 and 1.6% at the nucleotide level from strain AD169. Only 11 amino acids were found to vary in one or more viral strains, and these variations occurred only in the domains of pUL37x1 dispensable for its antiapoptotic function. We infer from this remarkable conservation of pUL37x1 in primary strains that this protein and, probably, its antiapoptotic function are required for productive replication of human cytomegalovirus in humans.

  4. Recognition Strategies of Group 3 Innate Lymphoid Cells

    PubMed Central

    Killig, Monica; Glatzer, Timor; Romagnani, Chiara

    2014-01-01

    During the early phase of an inflammatory response, innate cells can use different strategies to sense environmental danger. These include the direct interaction of specific activating receptors with pathogen-encoded/danger molecules or the engagement of cytokine receptors by pro-inflammatory mediators produced by antigen presenting cells in the course of the infection. These general recognition strategies, which have been extensively described for innate myeloid cells, are shared by innate lymphoid cells (ILC), such as Natural Killer (NK) cells. The family of ILC has recently expanded with the discovery of group 2 (ILC2) and group 3 ILC (ILC3), which play an important role in the defense against extracellular pathogens. Although ILC3 and NK cells share some phenotypic characteristics, the recognition strategies employed by the various ILC3 subsets have been only partially characterized. In this review, we will describe and comparatively discuss how ILC3 sense environmental cues and how the triggering of different receptors may regulate their functional behavior during an immune response. PMID:24744763

  5. Innate immunity, coagulation and placenta-related adverse pregnancy outcomes.

    PubMed

    Li, Min; Huang, S Joseph

    2009-12-01

    Maternal immunity undergoes subtle adjustment in order to tolerate the semi-allogeneic embryo and maintain the host defense against potential pathogens. Concomitantly, coagulation systems change from an anti-coagulant state to a pro-coagulant state to meet the hemostatic challenge of placentation and delivery. Innate immunity and blood coagulation systems are the first line of defense to protect a host against exogenous challenges, including alloantigens and mechanical insults, and preserve the integrity of an organism. The interactions between coagulation and immune systems have been extensively studied. Immune cells play a pivotal role in the initiation of the coagulation cascade, whereas coagulation proteases display substantial immuno-modulatory effects. Upon exogenous challenges, the immune and coagulation systems are capable of potentiating each other leading to a vicious cycle. Natural killer (NK) cells, macrophages (Mphis) and dendritic cells (DCs) are three major innate immune cells that have been demonstrated to play essential roles in early pregnancy. However, immune maladaptation and hemostatic imbalance have been suggested to be responsible for adverse pregnant outcomes, such as preeclampsia (PE), miscarriage, recurrent spontaneous abortion (RSA) and intrauterine growth restriction (IUGR). In this review, we will summarize the mutual regulation between blood coagulation and innate immune systems as well as their roles in the maintenance of normal pregnancy and in the pathogenesis of adverse pregnancy outcomes.

  6. Is Ki-67 Expression Prognostic for Local Relapse in Early-Stage Breast Cancer Patients Treated With Breast Conservation Therapy (BCT)?

    SciTech Connect

    Hafeez, Farhaan; Neboori, Hanmanth J.; Harigopal, Malini; Wu, Hao; Haffty, Bruce G.; Yang, Qifeng; Schiff, Devora; Moran, Meena S.

    2013-10-01

    Purpose: Ki-67 is a human nuclear protein whose expression is strongly up-regulated in proliferating cells and can be used to determine the growth fraction in clonal cell populations. Although there are some data to suggest that Ki-67 overexpression may be prognostic for endpoints such as survival or postmastectomy recurrence, further elucidation of its prognostic significance is warranted. Specifically after breast conservation therapy (BCT) (defined in this setting as breast-conserving surgery and adjuvant radiation therapy), whether Ki-67 predicts for locoregional recurrence has not been investigated. The purpose of this study was to assess Ki-67 expression in a cohort of early-stage breast cancer patients to determine whether a significant independent association between Ki-67 and locoregional relapse exists. Methods and Materials: Ki-67 staining was conducted on a tissue microarray of 438 patients previously treated with BCT, and expression was analyzed with clinicopathologic features and outcomes from our database. Results: Ki-67 expression was more prevalent in black patients (37% of black patients vs 17% of white patients, P<.01), younger patients (27% of patients aged ≤50 years vs 15% of patients aged >50 years, P<.01), estrogen receptor (ER)–negative tumors (25% of ER-negative tumors vs 17% of ER-positive tumors, P=.04), human epidermal growth factor receptor 2 (HER2)/neu–positive tumors (35% of HER2-positive tumors vs 18% of HER2-negative tumors, P=.01), and larger tumors (26% of T2 tumors vs 16% of T1 tumors, P=.03). On univariate/multivariate analysis, Ki-67 did not predict for overall survival (74.4% vs 72.6%), cause-specific survival (82.9% vs 82.1%), local relapse-free survival (83.6% vs 88.5%), distant metastasis-free survival (76.1% vs 81.4%), recurrence-free survival (65.5% vs 74.6%), and locoregional recurrence-free survival (81.6% vs 84.7%): P>.05 for all. Conclusions: Ki-67 appears to be a surrogate marker for aggressive disease and

  7. Does baseline innate immunity change with age? A multi-year study in great tits.

    PubMed

    Vermeulen, Anke; Eens, Marcel; Van Dongen, Stefan; Müller, Wendt

    2017-03-16

    Throughout their life animals progressively accumulate mostly detrimental changes in cells, tissues and their functions, causing a decrease in individual performance and ultimately an increased risk of death. The latter may be amplified if it also leads to a deterioration of the immune system which forms the most important protection against the permanent threat of pathogens and infectious diseases. Here, we investigated how four baseline innate immune parameters (natural antibodies, complement activity, concentrations of haptoglobin and concentrations of nitric oxide) changed with age in free-living great tits (Parus major). We applied both cross-sectional and longitudinal approaches as birds were sampled for up to three years of their lives. Three out of the four selected innate immune parameters were affected by age. However, the shape of the response curves differed strongly among the innate immune parameters. Natural antibody levels increased during early life until mid-age to decrease thereafter when birds aged. Complement activity was highest in young birds, while levels slightly decreased with increasing age. Haptoglobin levels on the other hand, showed a linear, but highly variable increase with age, while nitric oxide concentrations were unaffected by age. The observed differences among the four studied innate immune traits not only indicate the importance of considering several immune traits at the same time, but also highlight the complexity of innate immunity. Unraveling the functional significance of the observed changes in innate immunity is thus a challenging next step.

  8. Trade-offs between acquired and innate immune defenses in humans

    PubMed Central

    McDade, Thomas W.; Georgiev, Alexander V.; Kuzawa, Christopher W.

    2016-01-01

    Immune defenses provide resistance against infectious disease that is critical to survival. But immune defenses are costly, and limited resources allocated to immunity are not available for other physiological or developmental processes. We propose a framework for explaining variation in patterns of investment in two important subsystems of anti-pathogen defense: innate (non-specific) and acquired (specific) immunity. The developmental costs of acquired immunity are high, but the costs of maintenance and activation are relatively low. Innate immunity imposes lower upfront developmental costs, but higher operating costs. Innate defenses are mobilized quickly and are effective against novel pathogens. Acquired responses are less effective against novel exposures, but more effective against secondary exposures due to immunological memory. Based on their distinct profiles of costs and effectiveness, we propose that the balance of investment in innate versus acquired immunity is variable, and that this balance is optimized in response to local ecological conditions early in development. Nutritional abundance, high pathogen exposure and low signals of extrinsic mortality risk during sensitive periods of immune development should all favor relatively higher levels of investment in acquired immunity. Undernutrition, low pathogen exposure, and high mortality risk should favor innate immune defenses. The hypothesis provides a framework for organizing prior empirical research on the impact of developmental environments on innate and acquired immunity, and suggests promising directions for future research in human ecological immunology. PMID:26739325

  9. Crosstalk between innate and adaptive immunity in hepatitis B virus infection.

    PubMed

    Wang, Li; Wang, Kai; Zou, Zhi-Qiang

    2015-12-28

    Hepatitis B virus (HBV) infection is a major public health problem worldwide. HBV is not directly cytotoxic to infected hepatocytes; the clinical outcome of infection results from complicated interactions between the virus and the host immune system. In acute HBV infection, initiation of a broad, vigorous immune response is responsible for viral clearance and self-limited inflammatory liver disease. Effective and coordinated innate and adaptive immune responses are critical for viral clearance and the development of long-lasting immunity. Chronic hepatitis B patients fail to mount efficient innate and adaptive immune responses to the virus. In particular, HBV-specific cytotoxic T cells, which are crucial for HBV clearance, are hyporesponsiveness to HBV infection. Accumulating experimental evidence obtained from the development of animal and cell line models has highlighted the importance of innate immunity in the early control of HBV spread. The virus has evolved immune escape strategies, with higher HBV loads and HBV protein concentrations associated with increasing impairment of immune function. Therefore, treatment of HBV infection requires inhibition of HBV replication and protein expression to restore the suppressed host immunity. Complicated interactions exist not only between innate and adaptive responses, but also among innate immune cells and different components of adaptive responses. Improved insight into these complex interactions are important in designing new therapeutic strategies for the treatment HBV infection. In this review, we summarize the current knowledge regarding the cross-talk between the innate and adaptive immune responses and among different immunocytes in HBV infection.

  10. Crosstalk between innate and adaptive immunity in hepatitis B virus infection

    PubMed Central

    Wang, Li; Wang, Kai; Zou, Zhi-Qiang

    2015-01-01

    Hepatitis B virus (HBV) infection is a major public health problem worldwide. HBV is not directly cytotoxic to infected hepatocytes; the clinical outcome of infection results from complicated interactions between the virus and the host immune system. In acute HBV infection, initiation of a broad, vigorous immune response is responsible for viral clearance and self-limited inflammatory liver disease. Effective and coordinated innate and adaptive immune responses are critical for viral clearance and the development of long-lasting immunity. Chronic hepatitis B patients fail to mount efficient innate and adaptive immune responses to the virus. In particular, HBV-specific cytotoxic T cells, which are crucial for HBV clearance, are hyporesponsiveness to HBV infection. Accumulating experimental evidence obtained from the development of animal and cell line models has highlighted the importance of innate immunity in the early control of HBV spread. The virus has evolved immune escape strategies, with higher HBV loads and HBV protein concentrations associated with increasing impairment of immune function. Therefore, treatment of HBV infection requires inhibition of HBV replication and protein expression to restore the suppressed host immunity. Complicated interactions exist not only between innate and adaptive responses, but also among innate immune cells and different components of adaptive responses. Improved insight into these complex interactions are important in designing new therapeutic strategies for the treatment HBV infection. In this review, we summarize the current knowledge regarding the cross-talk between the innate and adaptive immune responses and among different immunocytes in HBV infection. PMID:26730277

  11. Innate immunesenescence: underlying mechanisms and clinical relevance.

    PubMed

    Hazeldine, Jon; Lord, Janet M

    2015-04-01

    A well-established feature of physiological ageing is altered immune function, a phenomenon termed immunesenescence. Thought to be responsible in part for the increased incidence and severity of infection reported by older adults, as well as the age-related decline in vaccine efficacy and autoimmunity, immunesenescence affects both the innate and adaptive arms of the immune system. Whilst much is known regarding the impact of age on adaptive immunity, innate immunity has received far less attention from immune gerontologists. However, over the last decade it has become increasingly apparent that this non-specific arm of the immune response undergoes considerable functional and phenotypical alterations with age. Here, we provide a detailed overview of innate immunesenescence and its underlying molecular mechanisms, and highlight those studies whose results indicate that changes in innate immunity with age have a significant impact upon the health and well-being of older adults.

  12. New thinking, innateness and inherited representation.

    PubMed

    Shea, Nicholas

    2012-08-05

    The New Thinking contained in this volume rejects an Evolutionary Psychology that is committed to innate domain-specific psychological mechanisms: gene-based adaptations that are unlearnt, developmentally fixed and culturally universal. But the New Thinking does not simply deny the importance of innate psychological traits. The problem runs deeper: the concept of innateness is not suited to distinguishing between the New Thinking and Evolutionary Psychology. That points to a more serious problem with the concept of innateness as it is applied to human psychological phenotypes. This paper argues that the features of recent human evolution highlighted by the New Thinking imply that the concept of inherited representation, set out here, is a better tool for theorizing about human cognitive evolution.

  13. Viral Inhibition of PRR-Mediated Innate Immune Response: Learning from KSHV Evasion Strategies

    PubMed Central

    Lee, Hye-Ra; Choi, Un Yung; Hwang, Sung-Woo; Kim, Stephanie; Jung, Jae U.

    2016-01-01

    The innate immune system has evolved to detect and destroy invading pathogens before they can establish systemic infection. To successfully eradicate pathogens, including viruses, host innate immunity is activated through diverse pattern recognition receptors (PRRs) which detect conserved viral signatures and trigger the production of type I interferon (IFN) and pro-inflammatory cytokines to mediate viral clearance. Viral persistence requires that viruses co-opt cellular pathways and activities for their benefit. In particular, due to the potent antiviral activities of IFN and cytokines, viruses have developed various strategies to meticulously modulate intracellular innate immune sensing mechanisms to facilitate efficient viral replication and persistence. In this review, we highlight recent advances in the study of viral immune evasion strategies with a specific focus on how Kaposi’s sarcoma-associated herpesvirus (KSHV) effectively targets host PRR signaling pathways. PMID:27871174

  14. Viral Inhibition of PRR-Mediated Innate Immune Response: Learning from KSHV Evasion Strategies.

    PubMed

    Lee, Hye-Ra; Choi, Un Yung; Hwang, Sung-Woo; Kim, Stephanie; Jung, Jae U

    2016-11-30

    The innate immune system has evolved to detect and destroy invading pathogens before they can establish systemic infection. To successfully eradicate pathogens, including viruses, host innate immunity is activated through diverse pattern recognition receptors (PRRs) which detect conserved viral signatures and trigger the production of type I interferon (IFN) and pro-inflammatory cytokines to mediate viral clearance. Viral persistence requires that viruses co-opt cellular pathways and activities for their benefit. In particular, due to the potent antiviral activities of IFN and cytokines, viruses have developed various strategies to meticulously modulate intracellular innate immune sensing mechanisms to facilitate efficient viral replication and persistence. In this review, we highlight recent advances in the study of viral immune evasion strategies with a specific focus on how Kaposi's sarcoma-associated herpesvirus (KSHV) effectively targets host PRR signaling pathways.

  15. Bacteria fighting back: how pathogens target and subvert the host innate immune system.

    PubMed

    Reddick, L Evan; Alto, Neal M

    2014-04-24

    The innate immune system has evolved under selective pressure since the radiation of multicellular life approximately 600 million years ago. Because of this long history, innate immune mechanisms found in modern eukaryotic organisms today are highly complex but yet built from common molecular strategies. It is now clear that evolution has selected a conserved set of antimicrobial peptides as well as pattern-recognition receptors (PRRs) that initiate cellular-based signals as a first line of defense against invading pathogens. Conversely, microbial pathogens employ their own strategies in order to evade, inhibit, or otherwise manipulate the innate immune response. Here, we discuss recent discoveries that have changed our view of immune modulatory mechanisms employed by bacterial pathogens, focusing specifically on the initial sites of microbial recognition and extending to host cellular signal transduction, proinflammatory cytokine production, and alteration of protein trafficking and secretion.

  16. Innate Immune Sensing and Response to Influenza

    PubMed Central

    Pulendran, Bali; Maddur, Mohan S.

    2015-01-01

    Influenza viruses pose a substantial threat to human and animal health worldwide. Recent studies in mouse models have revealed an indispensable role for the innate immune system in defense against influenza virus. Recognition of the virus by innate immune receptors in a multitude of cell types activates intricate signaling networks, functioning to restrict viral replication. Downstream effector mechanisms include activation of innate immune cells and, induction and regulation of adaptive immunity. However, uncontrolled innate responses are associated with exaggerated disease, especially in pandemic influenza virus infection. Despite advances in the understanding of innate response to influenza in the mouse model, there is a large knowledge gap in humans, particularly in immunocom-promised groups such as infants and the elderly. We propose here, the need for further studies in humans to decipher the role of innate immunity to influenza virus, particularly at the site of infection. These studies will complement the existing work in mice and facilitate the quest to design improved vaccines and therapeutic strategies against influenza. PMID:25078919

  17. Identification of conserved microRNAs in peripheral blood from giant panda: expression of mammary gland-related microRNAs during late pregnancy and early lactation.

    PubMed

    Wang, C D; Long, K; Jin, L; Huang, S; Li, D H; Ma, X P; Wei, M; Gu, Y; Ma, J D; Zhang, H

    2015-11-13

    The giant panda (Ailuropoda melanoleuca) is one of the world's most endangered mammals, and it has evolved several unusual biological and behavioral traits. During puberty, pregnancy, lactation, and involution, the mammary gland undergoes profound morphological and functional changes. A large number of microRNAs (miRNAs) have been identified to be involved in mammary gland development and lactation. In this study, we identified 202 conserved mature miRNAs, corresponding to 147 pre-miRNAs, in giant panda peripheral blood using a small RNA-sequencing approach. In addition, 27 miRNA families and 29 miRNA clusters were identified. We analyzed the arm selection preference of pre-miRNAs and found that: 1) most giant panda pre-miRNAs generated one-strand miRNAs, and the 5p-arm only miRNAs have a higher expression level than 3p-arm only miRNAs; 2) there were more 5p-arm dominant miRNAs than 3p-arm dominant miRNAs; and 3) 5p-arm dominant miRNAs have a larger fold change within miRNA pairs than 3p-arm dominant miRNAs. Expression of 12 lactation-related miRNAs was detected across late pregnancy and early lactation stages by qPCR, and seven miRNAs were identified as clustered in one significant model. Most of these clustered miRNAs exhibited inhibitory roles in proliferation and differentiation of mammary epithelial cells. Functional analysis highlighted important roles of the seven as signed miRNAs in mammary development and metabolic changes, including blood vessel morphogenesis, macromolecule biosynthesis, cell cycle regulation, and protein transport.

  18. Amygdala EphB2 Signaling Regulates Glutamatergic Neuron Maturation and Innate Fear

    PubMed Central

    Zhu, Xiao-Na; Liu, Xian-Dong; Zhuang, Hanyi; Henkemeyer, Mark

    2016-01-01

    The amygdala serves as emotional center to mediate innate fear behaviors that are reflected through neuronal responses to environmental aversive cues. However, the molecular mechanism underlying the initial neuron responses is poorly understood. In this study, we monitored the innate defensive responses to aversive stimuli of either elevated plus maze or predator odor in juvenile mice and found that glutamatergic neurons were activated in amygdala. Loss of EphB2, a receptor tyrosine kinase expressed in amygdala neurons, suppressed the reactions and led to defects in spine morphogenesis and fear behaviors. We further found a coupling of spinogenesis with these threat cues induced neuron activation in developing amygdala that was controlled by EphB2. A constitutively active form of EphB2 was sufficient to rescue the behavioral and morphological defects caused by ablation of ephrin-B3, a brain-enriched ligand to EphB2. These data suggest that kinase-dependent EphB2 intracellular signaling plays a major role for innate fear responses during the critical developing period, in which spinogenesis in amygdala glutamatergic neurons was involved. SIGNIFICANCE STATEMENT Generation of innate fear responses to threat as an evolutionally conserved brain feature relies on development of functional neural circuit in amygdala, but the molecular mechanism remains largely unknown. We here identify that EphB2 receptor tyrosine kinase, which is specifically expressed in glutamatergic neurons, is required for the innate fear responses in the neonatal brain. We further reveal that EphB2 mediates coordination of spinogenesis and neuron activation in amygdala during the critical period for the innate fear. EphB2 catalytic activity plays a major role for the behavior upon EphB–ephrin-B3 binding and transnucleus neuronal connections. Our work thus indicates an essential synaptic molecular signaling within amygdala that controls synapse development and helps bring about innate fear emotions

  19. Innate Visual Learning through Spontaneous Activity Patterns

    PubMed Central

    Albert, Mark V.; Schnabel, Adam; Field, David J.

    2008-01-01

    Patterns of spontaneous activity in the developing retina, LGN, and cortex are necessary for the proper development of visual cortex. With these patterns intact, the primary visual cortices of many newborn animals develop properties similar to those of the adult cortex but without the training benefit of visual experience. Previous models have demonstrated how V1 responses can be initialized through mechanisms specific to development and prior to visual experience, such as using axonal guidance cues or relying on simple, pairwise correlations on spontaneous activity with additional developmental constraints. We argue that these spontaneous patterns may be better understood as part of an “innate learning” strategy, which learns similarly on activity both before and during visual experience. With an abstraction of spontaneous activity models, we show how the visual system may be able to bootstrap an efficient code for its natural environment prior to external visual experience, and we continue the same refinement strategy upon natural experience. The patterns are generated through simple, local interactions and contain the same relevant statistical properties of retinal waves and hypothesized waves in the LGN and V1. An efficient encoding of these patterns resembles a sparse coding of natural images by producing neurons with localized, oriented, bandpass structure—the same code found in early visual cortical cells. We address the relevance of higher-order statistical properties of spontaneous activity, how this relates to a system that may adapt similarly on activity prior to and during natural experience, and how these concepts ultimately relate to an efficient coding of our natural world. PMID:18670593

  20. Expanding the universe of cytokines and pattern recognition receptors: galectins and glycans in innate immunity.

    PubMed

    Cerliani, Juan P; Stowell, Sean R; Mascanfroni, Iván D; Arthur, Connie M; Cummings, Richard D; Rabinovich, Gabriel A

    2011-02-01

    Effective immunity relies on the recognition of pathogens and tumors by innate immune cells through diverse pattern recognition receptors (PRRs) that lead to initiation of signaling processes and secretion of pro- and anti-inflammatory cytokines. Galectins, a family of endogenous lectins widely expressed in infected and neoplastic tissues have emerged as part of the portfolio of soluble mediators and pattern recognition receptors responsible for eliciting and controlling innate immunity. These highly conserved glycan-binding proteins can control immune cell processes through binding to specific glycan structures on pathogens and tumors or by acting intracellularly via modulation of selective signaling pathways. Recent findings demonstrate that various galectin family members influence the fate and physiology of different innate immune cells including polymorphonuclear neutrophils, mast cells, macrophages, and dendritic cells. Moreover, several pathogens may actually utilize galectins as a mechanism of host invasion. In this review, we aim to highlight and integrate recent discoveries that have led to our current understanding of the role of galectins in host-pathogen interactions and innate immunity. Challenges for the future will embrace the rational manipulation of galectin-glycan interactions to instruct and shape innate immunity during microbial infections, inflammation, and cancer.

  1. Natural killer T cells: innate lymphocytes positioned as a bridge between acute and chronic inflammation?

    PubMed Central

    Fox, Lisa; Hegde, Subramanya

    2010-01-01

    Natural killer T cells are an innate population of T lymphocytes that recognize antigens derived from host lipids and glycolipids. In this review, we focus on how these unique T cells are positioned to influence both acute and chronic inflammatory processes through their early recruitment to sites of inflammation, interactions with myeloid antigen presenting cells, and recognition of lipids associated with inflammation. PMID:20850561

  2. Innate immune inflammatory response in the acutely ischemic myocardium.

    PubMed

    Deftereos, Spyridon; Angelidis, Christos; Bouras, Georgios; Raisakis, Konstantinos; Gerckens, Ulrich; Cleman, Michael W; Giannopoulos, Georgios

    2014-01-01

    The "holy grail" of modern interventional cardiology is the salvage of viable myocardial tissue in the distribution of an acutely occluded coronary artery. Thrombolysis and percutaneous coronary interventions, provided they can be delivered on time, can interrupt the occlusion and save tissue. At the same time restoring the patency of the coronary vessels and providing the ischemic myocardium with blood can cause additional tissue damage. A key element of ischemic and reperfusion injury and major determinant of the evolution of damage in the injured myocardium is the inflammatory response. The innate immune system initiates and directs this response which is a prerequisite for subsequent healing. The complement cascade is set in motion following the release of subcellular membrane constituents. Endogenous 'danger' signals known as danger-associated molecular patterns (DAMPs) released from ischemic and dying cells alert the innate immune system and activate several signal transduction pathways through interactions with the highly conserved Toll like receptors (TLRs). Reactive oxygen species (ROS) generation directly induces pro-inflammatory cascades and triggers formation of the inflammasome. The challenge lies into designing strategies that specifically block the inflammatory cascades responsible for tissue damage without affecting those concerned with tissue healing.

  3. Innate immunity probed by lipopolysaccharides affinity strategy and proteomics.

    PubMed

    Giangrande, Chiara; Colarusso, Lucia; Lanzetta, Rosa; Molinaro, Antonio; Pucci, Piero; Amoresano, Angela

    2013-01-01

    Lipopolysaccharides (LPSs) are ubiquitous and vital components of the cell surface of Gram-negative bacteria that have been shown to play a relevant role in the induction of the immune-system response. In animal and plant cells, innate immune defenses toward microorganisms are triggered by the perception of pathogen associated molecular patterns. These are conserved and generally indispensable microbial structures such as LPSs that are fundamental in the Gram-negative immunity recognition. This paper reports the development of an integrated strategy based on lipopolysaccharide affinity methodology that represents a new starting point to elucidate the molecular mechanisms elicited by bacterial LPS and involved in the different steps of innate immunity response. Biotin-tagged LPS was immobilized on streptavidin column and used as a bait in an affinity capture procedure to identify protein partners from human serum specifically interacting with this effector. The complex proteins/lipopolysaccharide was isolated and the protein partners were fractionated by gel electrophoresis and identified by mass spectrometry. This procedure proved to be very effective in specifically binding proteins functionally correlated with the biological role of LPS. Proteins specifically bound to LPS essentially gathered within two functional groups, regulation of the complement system (factor H, C4b, C4BP, and alpha 2 macroglobulin) and inhibition of LPS-induced inflammation (HRG and Apolipoproteins). The reported strategy might have important applications in the elucidation of biological mechanisms involved in the LPSs-mediated molecular recognition and anti-infection responses.

  4. Innateness and the instinct to learn.

    PubMed

    Marler, Peter

    2004-06-01

    Concepts of innateness were at the heart of Darwin's approach to behavior and central to the ethological theorizing of Lorenz and, at least to start with, of Tinbergen. Then Tinbergen did an about face, and for some twenty years the term 'innate' became highly suspect. He attributed the change to Lehrman's famous 1953 critique in which he asserted that classifying behaviors as innate tells us nothing about how they develop. Although Lehrman made many valid points, I will argue that this exchange also led to profound misunderstandings that were ultimately damaging to progress in research on the development of behavior. The concept of 'instincts to learn', receiving renewed support from current theorizing among geneticists about phenotypic plasticity, provides a potential resolution of some of the controversies that Lehrman created. Bioacoustical studies, particularly on song learning in birds, serve both to confirm some of Lehrman's anxieties about the term 'innate', but also to make a case that he threw out the genetic baby with the bathwater. The breathtaking progress in molecular and developmental genetics has prepared the way for a fuller understanding of the complexities underlying even the simplest notions of innate behavior, necessary before we can begin to comprehend the ontogeny of behavior.

  5. Corruption of Innate Immunity by Bacterial Proteases

    PubMed Central

    Potempa, Jan; Pike, Robert N.

    2009-01-01

    The innate immune system of the human body has developed numerous mechanisms to control endogenous and exogenous bacteria and thus prevent infections by these microorganisms. These mechanisms range from physical barriers such as the skin or mucosal epithelium to a sophisticated array of molecules and cells that function to suppress or prevent bacterial infection. Many bacteria express a variety of proteases, ranging from non-specific and powerful enzymes that degrade many proteins involved in innate immunity to proteases that are extremely precise and specific in their mode of action. Here we have assembled a comprehensive picture of how bacterial proteases affect the host’s innate immune system to gain advantage and cause infection. This picture is far from being complete since the numbers of mechanisms utilized are as astonishing as they are diverse, ranging from degradation of molecules vital to innate immune mechanisms to subversion of the mechanisms to allow the bacterium to hide from the system or take advantage of it. It is vital that such mechanisms are elucidated to allow strategies to be developed to aid the innate immune system in controlling bacterial infections. PMID:19756242

  6. Corruption of innate immunity by bacterial proteases.

    PubMed

    Potempa, Jan; Pike, Robert N

    2009-01-01

    The innate immune system of the human body has developed numerous mechanisms to control endogenous and exogenous bacteria and thus prevent infections by these microorganisms. These mechanisms range from physical barriers such as the skin or mucosal epithelium to a sophisticated array of molecules and cells that function to suppress or prevent bacterial infection. Many bacteria express a variety of proteases, ranging from non-specific and powerful enzymes that degrade many proteins involved in innate immunity to proteases that are extremely precise and specific in their mode of action. Here we have assembled a comprehensive picture of how bacterial proteases affect the host's innate immune system to gain advantage and cause infection. This picture is far from being complete since the numbers of mechanisms utilized are as astonishing as they are diverse, ranging from degradation of molecules vital to innate immune mechanisms to subversion of the mechanisms to allow the bacterium to hide from the system or take advantage of it. It is vital that such mechanisms are elucidated to allow strategies to be developed to aid the innate immune system in controlling bacterial infections.

  7. Innate Immunity and BK Virus: Prospective Strategies.

    PubMed

    Kariminik, Ashraf; Yaghobi, Ramin; Dabiri, Shahriar

    2016-03-01

    Recent information demonstrated that BK virus reactivation is a dominant complication after kidney transplantation, which occurs because of immunosuppression. BK virus reactivation is the main reason of transplanted kidney losing. Immune response against BK virus is the major inhibitor of the virus reactivation. Therefore, improving our knowledge regarding the main parameters that fight against BK viruses can shed light on to direct new treatment strategies to suppress BK infection. Innate immunity consists of numerous cell systems and also soluble molecules, which not only suppress virus replication, but also activate adaptive immunity to eradicate the infection. Additionally, it appears that immune responses against reactivated BK virus are the main reasons for induction of BK virus-associated nephropathy (BKAN). Thus, improving our knowledge regarding the parameters and detailed mechanisms of innate immunity and also the status of innate immunity of the patients with BK virus reactivation and its complications can introduce new prospective strategies to either prevent or as therapy of the complication. Therefore, this review was aimed to collate the most recent data regarding the roles played by innate immunity against BK virus and also the status of innate immunity in the patients with reactivation BK virus and BKAN.

  8. RNA-Seq of the Caribbean reef-building coral Orbicella faveolata (Scleractinia-Merulinidae) under bleaching and disease stress expands models of coral innate immunity.

    PubMed

    Anderson, David A; Walz, Marcus E; Weil, Ernesto; Tonellato, Peter; Smith, Matthew C

    2016-01-01

    Climate change-driven coral disease outbreaks have led to widespread declines in coral populations. Early work on coral genomics established that corals have a complex innate immune system, and whole-transcriptome gene expression studies have revealed mechanisms by which the coral immune system responds to stress and disease. The present investigation expands bioinformatic data available to study coral molecular physiology through the assembly and annotation of a reference transcriptome of the Caribbean reef-building coral, Orbicella faveolata. Samples were collected during a warm water thermal anomaly, coral bleaching event and Caribbean yellow band disease outbreak in 2010 in Puerto Rico. Multiplex sequencing of RNA on the Illumina GAIIx platform and de novo transcriptome assembly by Trinity produced 70,745,177 raw short-sequence reads and 32,463 O. faveolata transcripts, respectively. The reference transcriptome was annotated with gene ontologies, mapped to KEGG pathways, and a predicted proteome of 20,488 sequences was generated. Protein families and signaling pathways that are essential in the regulation of innate immunity across Phyla were investigated in-depth. Results were used to develop models of evolutionarily conserved Wnt, Notch, Rig-like receptor, Nod-like receptor, and Dicer signaling. O. faveolata is a coral species that has been studied widely under climate-driven stress and disease, and the present investigation provides new data on the genes that putatively regulate its immune system.

  9. Collections Conservation.

    ERIC Educational Resources Information Center

    DeCandido, Robert

    Collections conservation is an approach to the preservation treatment of books and book-like materials that is conceptualized and organized in terms of large groups of materials. This guide is intended to enable a library to evaluate its current collections conservation activities. The introduction describes collections conservation and gives…

  10. Margin status and the risk of local recurrence in patients with early-stage breast cancer treated with breast-conserving therapy.

    PubMed

    Russo, Andrea L; Arvold, Nils D; Niemierko, Andrzej; Wong, Nathan; Wong, Julia S; Bellon, Jennifer R; Punglia, Rinaa S; Golshan, Mehra; Troyan, Susan L; Brock, Jane E; Harris, Jay R

    2013-07-01

    We sought to assess whether a close surgical margin (>0 and <2 mm) after breast-conserving therapy (BCT) confers an increased risk of local recurrence (LR) compared with a widely negative margin (≥2 mm). We studied 906 women with early-stage invasive breast cancer treated with BCT between January 1998 and October 2006; 91 % received adjuvant systemic therapy. Margins were coded as: (1) widely negative (n = 729), (2) close (n = 85), or (3) close (n = 84)/positive (n = 8) but having no additional tissue to remove according to the surgeon. Cumulative incidence of LR and distant failure (DF) were calculated using the Kaplan-Meier method. Gray's competing-risk regression assessed the effect of margin status on LR and Cox proportional hazards regression assessed the effect on DF, controlling for biologic subtype, age, and number of positive lymph nodes (LNs). Three hundred seventy-seven patients (41.6 %) underwent surgical re-excision, of which 63.5 % had no residual disease. With a median follow-up of 87.5 months, the 5-year cumulative incidence of LR was 2.5 %. The 5-year cumulative incidence of LR by margin status was 2.3 % (95 % CI 1.4-3.8 %) for widely negative, 0 % for close, and 6.4 % (95 % CI 2.7-14.6 %) for no additional tissue, p = 0.3. On multivariate analysis, margin status was not associated with LR; however, triple-negative subtype (AHR 3.7; 95 % CI 1.6-8.8; p = 0.003) and increasing number of positive LNs (AHR 1.6; 95 % CI 1.1-2.3; p = 0.025) were associated. In an era of routine adjuvant systemic therapy, close surgical margins and maximally resected close/positive margins were not associated with an increased risk of LR compared to widely negative margins. Additional studies are needed to confirm this finding.

  11. The innate immune system in demyelinating disease.

    PubMed

    Mayo, Lior; Quintana, Francisco J; Weiner, Howard L

    2012-07-01

    Demyelinating diseases such as multiple sclerosis are chronic inflammatory autoimmune diseases with a heterogeneous clinical presentation and course. Both the adaptive and the innate immune systems have been suggested to contribute to their pathogenesis and recovery. In this review, we discuss the role of the innate immune system in mediating demyelinating diseases. In particular, we provide an overview of the anti-inflammatory or pro-inflammatory functions of dendritic cells, mast cells, natural killer (NK) cells, NK-T cells, γδ T cells, microglial cells, and astrocytes. We emphasize the interaction of astroctyes with the immune system and how this interaction relates to the demyelinating pathologies. Given the pivotal role of the innate immune system, it is possible that targeting these cells may provide an effective therapeutic approach for demyelinating diseases.

  12. Ion Channels in Innate and Adaptive Immunity

    PubMed Central

    Feske, Stefan; Wulff, Heike; Skolnik, Edward Y.

    2016-01-01

    Ion channels and transporters mediate the transport of charged ions across hydrophobic lipid membranes. In immune cells, divalent cations such as calcium, magnesium, and zinc have important roles as second messengers to regulate intracellular signaling pathways. By contrast, monovalent cations such as sodium and potassium mainly regulate the membrane potential, which indirectly controls the influx of calcium and immune cell signaling. Studies investigating human patients with mutations in ion channels and transporters, analysis of gene-targeted mice, or pharmacological experiments with ion channel inhibitors have revealed important roles of ionic signals in lymphocyte development and in innate and adaptive immune responses. We here review the mechanisms underlying the function of ion channels and transporters in lymphocytes and innate immune cells and discuss their roles in lymphocyte development, adaptive and innate immune responses, and autoimmunity, as well as recent efforts to develop pharmacological inhibitors of ion channels for immunomodulatory therapy. PMID:25861976

  13. Innate immunity in lophotrochozoans: the annelids.

    PubMed

    Salzet, Michel; Tasiemski, Aurélie; Cooper, Edwin

    2006-01-01

    Innate immunity plays a major role as a first defense against microbes. Effectors of the innate response include pattern recognition receptors (PRR), phagocytic cells, proteolytic cascades and peptides/proteins with antimicrobial properties. Each element of these events has been well studied in vertebrates and in some invertebrates such as annelids. From these different researches, it appears that mammalian innate immunity could be considered as a mosaic of invertebrate immune responses. Annelids belonging to the lophotrochozoans' group are primitive coelomates that possess specially developed cellular immunity against pathogens including phagocytosis, encapsulation and spontaneous cytotoxicity of coelomocytes against allogenic or xenogenic cells. They have also developed an important humoral immunity that is based on antimicrobial, hemolytic and clotting properties of their body fluid. In the present review, we will emphasize the different immunodefense strategies that adaptation has taken during the course of evolution of two classes of annelids i.e. oligochaetes and achaetes.

  14. Humoral innate immune response and disease

    PubMed Central

    Shishido, Stephanie N.; Varahan, Sriram; Yuan, Kai; Li, Xiangdong; Fleming, Sherry D.

    2012-01-01

    The humoral innate immune response consists of multiple components, including the naturally occurring antibodies (NAb), pentraxins and the complement and contact cascades. As soluble, plasma components, these innate proteins provide key elements in the prevention and control of disease. However, pathogens and cells with altered self proteins utilize multiple humoral components to evade destruction and promote pathogy. Many studies have examined the relationship between humoral immunity and autoimmune disorders. This review focuses on the interactions between the humoral components and their role in promoting the pathogenesis of bacterial and viral infections and chronic diseases such as atherosclerosis and cancer. Understanding the beneficial and detrimental aspects of the individual components and the interactions between proteins which regulate the innate and adaptive response will provide therapeutic targets for subsequent studies. PMID:22771788

  15. Innate Immune sensing of DNA viruses

    PubMed Central

    Rathinam, Vijay A. K.; Fitzgerald, Katherine A.

    2011-01-01

    DNA viruses are a significant contributor to human morbidity and mortality. The immune system protects against viral infections through coordinated innate and adaptive immune responses. While the antigen-specific adaptive mechanisms have been extensively studied, the critical contributions of innate immunity to anti-viral defenses have only been revealed in the very recent past. Central to these anti-viral defenses is the recognition of viral pathogens by a diverse set of germ-line encoded receptors that survey nearly all cellular compartments for the presence of pathogens. In this review, we discuss the recent advances in the innate immune sensing of DNA viruses and focus on the recognition mechanisms involved. PMID:21334037

  16. [Regulation of allergy by innate immune system].

    PubMed

    Kumagai, Yutaro; Akira, Shizuo

    2009-11-01

    Allergy is an immune disease including asthma. Activation of Th2 response, such as production of IL-4, IL-5 and IL-13 from CD4+ T cells and IgG1 or IgE from B cells is responsible for allergy. Activation of acquired immune system requires preceding activation of innate immunity, therefore innate immunity may control Th2 response and allergy. Recent studies revealed that dendritic cells, epithelial cells, and basophils play central roles in the initiation of Th2 response. In this review, we will summarize the current understanding on the control of Th2 and allergic responses by innate immune system, and discuss recent findings on house dust mite-induced allergic response based on these understandings.

  17. Vaccine adjuvants: putting innate immunity to work.

    PubMed

    Coffman, Robert L; Sher, Alan; Seder, Robert A

    2010-10-29

    Adjuvants enhance immunity to vaccines and experimental antigens by a variety of mechanisms. In the past decade, many receptors and signaling pathways in the innate immune system have been defined and these innate responses strongly influence the adaptive immune response. The focus of this review is to delineate the innate mechanisms by which adjuvants mediate their effects. We highlight how adjuvants can be used to influence the magnitude and alter the quality of the adaptive response in order to provide maximum protection against specific pathogens. Despite the impressive success of currently approved adjuvants for generating immunity to viral and bacterial infections, there remains a need for improved adjuvants that enhance protective antibody responses, especially in populations that respond poorly to current vaccines. However, the larger challenge is to develop vaccines that generate strong T cell immunity with purified or recombinant vaccine antigens.

  18. Ion channels in innate and adaptive immunity.

    PubMed

    Feske, Stefan; Wulff, Heike; Skolnik, Edward Y

    2015-01-01

    Ion channels and transporters mediate the transport of charged ions across hydrophobic lipid membranes. In immune cells, divalent cations such as calcium, magnesium, and zinc have important roles as second messengers to regulate intracellular signaling pathways. By contrast, monovalent cations such as sodium and potassium mainly regulate the membrane potential, which indirectly controls the influx of calcium and immune cell signaling. Studies investigating human patients with mutations in ion channels and transporters, analysis of gene-targeted mice, or pharmacological experiments with ion channel inhibitors have revealed important roles of ionic signals in lymphocyte development and in innate and adaptive immune responses. We here review the mechanisms underlying the function of ion channels and transporters in lymphocytes and innate immune cells and discuss their roles in lymphocyte development, adaptive and innate immune responses, and autoimmunity, as well as recent efforts to develop pharmacological inhibitors of ion channels for immunomodulatory therapy.

  19. Innate cellular responses to rotavirus infection.

    PubMed

    Holloway, Gavan; Coulson, Barbara S

    2013-06-01

    Rotavirus is a leading cause of severe dehydrating diarrhoea in infants and young children. Following rotavirus infection in the intestine an innate immune response is rapidly triggered. This response leads to the induction of type I and type III interferons (IFNs) and other cytokines, resulting in a reduction in viral replication. Here we review the current literature describing the detection of rotavirus infection by pattern recognition receptors within host cells, the subsequent molecular mechanisms leading to IFN and cytokine production, and the processes leading to reduced rotavirus replication and the development of protective immunity. Rotavirus countermeasures against innate responses, and their roles in modulating rotavirus replication in mice, also are discussed. By linking these different aspects of innate immunity, we provide a comprehensive overview of the host's first line of defence against rotavirus infection. Understanding these processes is expected to be of benefit in improving strategies to combat rotavirus disease.

  20. Innate Immune Activity in Glomerular Podocytes

    PubMed Central

    Xia, Hong; Bao, Wenduona; Shi, Shaolin

    2017-01-01

    Glomerular podocytes are specialized in structure and play an essential role in glomerular filtration. In addition, podocyte stress can initiate glomerular damage by inducing the injury of other glomerular cell types. Studies have shown that podocytes possess the property of immune cells and may be involved in adaptive immunity. Emerging studies have also shown that podocytes possess signaling pathways of innate immune responses and that innate immune responses often result in podocyte injury. More recently, mitochondrial-derived damage-associated molecular patterns (mtDAMPs) have been shown to play a critical role in a variety of pathological processes in cells. In the present mini-review, we summarize the recent advances in the studies of innate immunity and its pathogenic role in podocytes, particularly, from the perspective of mtDAMPs. PMID:28228761

  1. New insights into upper airway innate immunity

    PubMed Central

    Hariri, Benjamin M.

    2016-01-01

    Background: Protecting the upper airway from microbial infection is an important function of the immune system. Proper detection of these pathogens is paramount for sinonasal epithelial cells to be able to prepare a defensive response. Toll-like receptors and, more recently, bitter taste receptors and sweet taste receptors have been implicated as sensors able to detect the presence of these pathogens and certain compounds that they secrete. Activation of these receptors also triggers innate immune responses to prevent or counteract infection, including mucociliary clearance and the production and secretion of antimicrobial compounds (e.g., defensins). Objective: To provide an overview of the current knowledge of the role of innate immunity in the upper airway, the mechanisms by which it is carried out, and its clinical relevance. Methods: A literature review of the existing knowledge of the role of innate immunity in the human sinonasal cavity was performed. Results: Clinical and basic science studies have shown that the physical epithelial cell barrier, mucociliary clearance, and antimicrobial compound secretion play pivotal innate immune roles in defending the sinonasal cavity from infection. Clinical findings have also linked dysfunction of these defense mechanisms with diseases, such as chronic rhinosinusitis and cystic fibrosis. Recent discoveries have elucidated the significance of bitter and sweet taste receptors in modulating immune responses in the upper airway. Conclusion: Numerous innate immune mechanisms seem to work in a concerted fashion to keep the sinonasal cavity free of infection. Understanding sinonasal innate immune function and dysfunction in health and disease has important implications for patients with respiratory ailments, such as chronic rhinosinusitis and cystic fibrosis. PMID:27657896

  2. Identification and evolution of an NFAT gene involving Branchiostoma belcheri innate immunity.

    PubMed

    Song, Xiaojun; Hu, Jing; Jin, Ping; Chen, Liming; Ma, Fei

    2013-10-01

    The Nuclear Factor of Activated T cells (NFAT) plays an important role in innate and adaptive immunity, but no NFAT genes have yet been identified in amphioxus species. Here we identified and characterized an NFAT-like gene from Branchiostoma belcheri, and also studied extensively the evolutionary history of NFAT family genes. We found that the amphioxus genome contains an AmphiNFAT gene encoding an NFAT homolog. The AmphiNFAT gene was found to be involved in the innate immune response to LPS stimulation in B. belcheri and was ubiquitously and differentially expressed in all investigated tissues. The NFAT family genes were present in a common ancestor with cnidaria, and NFAT1-4 paralogs were lost early in Branchiostoma and Strongylocentrotus genomes. We discovered that NFAT family genes underwent strong purifying selection. Taken together, our findings provide an insight into the innate immune response of amphioxus and the evolution of the NFAT gene family.

  3. Immunological memory within the innate immune system

    PubMed Central

    Sun, Joseph C; Ugolini, Sophie; Vivier, Eric

    2014-01-01

    Immune memory has traditionally been the domain of the adaptive immune system, present only in antigen-specific T and B cells. The purpose of this review is to summarize the evidence for immunological memory in lower organisms (which are not thought to possess adaptive immunity) and within specific cell subsets of the innate immune system. A special focus will be given to recent findings in both mouse and humans for specificity and memory in natural killer (NK) cells, which have resided under the umbrella of innate immunity for decades. The surprising longevity and enhanced responses of previously primed NK cells will be discussed in the context of several immunization settings. PMID:24674969

  4. Epithelial Innate Immune Response to Acinetobacter baumannii Challenge

    PubMed Central

    Feng, Zhimin; Jia, Xun; Adams, Mark D.; Ghosh, Santosh K.; Bonomo, Robert A.

    2014-01-01

    Currently, Acinetobacter baumannii is recognized as one of the major pathogens seriously threatening our health care delivery system. Aspects of the innate immune response to A. baumannii infection are not yet well understood. Human β-defensins (hBDs) are epithelial cell-derived cationic antimicrobial peptides (AMPs) that also function to bridge the innate and adaptive immune system. We tested the induction of hBD-2 and -3 by A. baumannii on primary oral and skin epithelial cells and found that A. baumannii induces hBD-3 transcripts to a greater extent than it induces hBD-2 transcripts on both types of cells. In addition, we found that A. baumannii is susceptible to hBD-2 and -3 killing at submicromolar concentrations. Moreover, hBD-3 induction by A. baumannii was found to be dependent on epidermal growth factor receptor (EGFR) signaling. Inhibition of mitogen-activated protein kinase resulted in reduced expression of both hBD-2 and -3. Lastly, a disintegrin and metalloprotease 17 (ADAM17; also known as TACE) was found to be critical for hBD-3 induction, while ADAM10 and dual oxidase 1 (Duox1) were not required for hBD-3 induction. Induction of AMPs is an important component of innate sensing of pathogens and may play an important role in triggering systemic immune responses to A. baumannii infection. Further studies on the interactions between epithelial cells and A. baumannii will help us understand early stages of infection and may shed light on why some individuals are more vulnerable to A. baumannii infection. PMID:25114113

  5. Epithelial innate immune response to Acinetobacter baumannii challenge.

    PubMed

    Feng, Zhimin; Jia, Xun; Adams, Mark D; Ghosh, Santosh K; Bonomo, Robert A; Weinberg, Aaron

    2014-11-01

    Currently, Acinetobacter baumannii is recognized as one of the major pathogens seriously threatening our health care delivery system. Aspects of the innate immune response to A. baumannii infection are not yet well understood. Human β-defensins (hBDs) are epithelial cell-derived cationic antimicrobial peptides (AMPs) that also function to bridge the innate and adaptive immune system. We tested the induction of hBD-2 and -3 by A. baumannii on primary oral and skin epithelial cells and found that A. baumannii induces hBD-3 transcripts to a greater extent than it induces hBD-2 transcripts on both types of cells. In addition, we found that A. baumannii is susceptible to hBD-2 and -3 killing at submicromolar concentrations. Moreover, hBD-3 induction by A. baumannii was found to be dependent on epidermal growth factor receptor (EGFR) signaling. Inhibition of mitogen-activated protein kinase resulted in reduced expression of both hBD-2 and -3. Lastly, a disintegrin and metalloprotease 17 (ADAM17; also known as TACE) was found to be critical for hBD-3 induction, while ADAM10 and dual oxidase 1 (Duox1) were not required for hBD-3 induction. Induction of AMPs is an important component of innate sensing of pathogens and may play an important role in triggering systemic immune responses to A. baumannii infection. Further studies on the interactions between epithelial cells and A. baumannii will help us understand early stages of infection and may shed light on why some individuals are more vulnerable to A. baumannii infection.

  6. Phenotype of NK-Like CD8(+) T Cells with Innate Features in Humans and Their Relevance in Cancer Diseases

    PubMed Central

    Barbarin, Alice; Cayssials, Emilie; Jacomet, Florence; Nunez, Nicolas Gonzalo; Basbous, Sara; Lefèvre, Lucie; Abdallah, Myriam; Piccirilli, Nathalie; Morin, Benjamin; Lavoue, Vincent; Catros, Véronique; Piaggio, Eliane; Herbelin, André; Gombert, Jean-Marc

    2017-01-01

    Unconventional T cells are defined by their capacity to respond to signals other than the well-known complex of peptides and major histocompatibility complex proteins. Among the burgeoning family of unconventional T cells, innate-like CD8(+) T cells in the mouse were discovered in the early 2000s. This subset of CD8(+) T cells bears a memory phenotype without having encountered a foreign antigen and can respond to innate-like IL-12 + IL-18 stimulation. Although the concept of innate memory CD8(+) T cells is now well established in mice, whether an equivalent memory NK-like T-cell population exists in humans remains under debate. We recently reported that CD8(+) T cells responding to innate-like IL-12 + IL-18 stimulation and co-expressing the transcription factor Eomesodermin (Eomes) and KIR/NKG2A membrane receptors with a memory/EMRA phenotype may represent a new, functionally distinct innate T cell subset in humans. In this review, after a summary on the known innate CD8(+) T-cell features in the mouse, we propose Eomes together with KIR/NKG2A and CD49d as a signature to standardize the identification of this innate CD8(+) T-cell subset in humans. Next, we discuss IL-4 and IL-15 involvement in the generation of innate CD8(+) T cells and particularly its possible dependency on the promyelocytic leukemia zinc-finger factor expressing iNKT cells, an innate T cell subset well documented for its susceptibility to tumor immune subversion. After that, focusing on cancer diseases, we provide new insights into the potential role of these innate CD8(+) T cells in a physiopathological context in humans. Based on empirical data obtained in cases of chronic myeloid leukemia, a myeloproliferative syndrome controlled by the immune system, and in solid tumors, we observe both the possible contribution of innate CD8(+) T cells to cancer disease control and their susceptibility to tumor immune subversion. Finally, we note that during tumor progression, innate CD8(+) T

  7. Wakayama symposium: interface between innate and adaptive immunity in dry eye disease.

    PubMed

    Na, Kyung-Sun; Hwang, Kyu-Yeon; Lee, Hyun-Soo; Chung, So-Hyang; Mok, Jee Won; Joo, Choun-Ki

    2015-12-17

    Although the mechanism of dry eye disease is not clearly understood, it is certain that inflammation and the immune response play a major role in determining the health of the ocular surface in dry eye patients. Accurate ocular surface characterization during the early stages of dry eye disease is critical for successful treatment, because there exists no single standard, objective test to diagnose the early phase of dry eye disease. The treatment target should be direct to prevent the perpetuation of chronic inflammation and immune responses. Numerous studies have categorized dry eye disease as an autoimmune-related inflammatory disease. However, relatively little is known about how innate immune mechanisms act following a local insult, why some patients are particularly vulnerable, and why local inflammation fails to resolve in these patients. Within this review, particular attention will be given to the very early events and corresponding defense mechanism in dry eye disease. The transition from innate to adaptive immunity will also be discussed.

  8. Etiology of myasthenia gravis: innate immunity signature in pathological thymus.

    PubMed

    Cavalcante, Paola; Cufi, Perrine; Mantegazza, Renato; Berrih-Aknin, Sonia; Bernasconi, Pia; Le Panse, Rozen

    2013-07-01

    Myasthenia gravis (MG) is an autoimmune disease affecting the neuromuscular junction (NMJ), whose clinical hallmark is muscle weakness and early fatigability. The main target of autoimmunity in MG is the acetylcholine receptor (AChR) located in the NMJ. It is now widely accepted that the thymus is probably the prime site of autoimmunity development and maintenance in AChR-positive MG patients; however, the exact mechanisms triggering and perpetuating the intra-thymic autoimmune response to AChR are still unknown. As with many autoimmune diseases, MG has a multifactorial etiology, resulting from complex interactions between genetic and environmental factors, as fully described in this review. Among environmental factors, viral infections could play a central role in autoimmunity, mainly through the induction of dysregulated Toll-like receptor (TLR)-mediated innate immune responses, which can lead to inflammation and adaptive autoimmune response. Growing evidence of chronic inflammation, TLR activation, and persistent viral infections in the thymus of MG patients, strongly supports the hypothesis that, in the context of a genetic susceptible background, the intrathymic innate immune responses to pathogen infections might contribute to MG etiology.

  9. Innate immunity against Legionella pneumophila during pulmonary infections in mice.

    PubMed

    Park, Bonggoo; Park, Gayoung; Kim, Jiyoung; Lim, Seon Ah; Lee, Kyung-Mi

    2017-02-01

    Legionella pneumophila is an etiological agent of the severe pneumonia known as Legionnaires' disease (LD). This gram-negative bacterium is thought to replicate naturally in various freshwater amoebae, but also replicates in human alveolar macrophages. Inside host cells, legionella induce the production of non-endosomal replicative phagosomes by injecting effector proteins into the cytosol. Innate immune responses are first line defenses against legionella during early phases of infection, and distinguish between legionella and host cells using germline-encoded pattern recognition receptors such as Toll-like receptors , NOD-like receptors, and RIG-I-like receptors, which sense pathogen-associated molecular patterns that are absent in host cells. During pulmonary legionella infections, various inflammatory cells such as macrophages, neutrophils, natural killer (NK) cells, large mononuclear cells, B cells, and CD4+ and CD8+ T cells are recruited into infected lungs, and predominantly occupy interstitial areas to control legionella. During pulmonary legionella infections, the interplay between distinct cytokines and chemokines also modulates innate host responses to clear legionella from the lungs. Recognition by NK cell receptors triggers effector functions including secretion of cytokines and chemokines, and leads to lysis of target cells. Crosstalk between NK cells and dendritic cells, monocytes, and macrophages provides a major first-line defense against legionella infection, whereas activation of T and B cells resolves the infection and mounts legionella-specific memory in the host.

  10. When less means more: dehydration improves innate immunity in rattlesnakes.

    PubMed

    Brusch, George A; DeNardo, Dale F

    2017-04-12

    Immune function can vary based on availability of resources, and most studies of such influences have focused on the co-investment of energy into immune and other physiological functions. When energy resources are limited, trade-offs exist, which can compromise immunity for other functions. As with energy, water limitation can also alter various physiological processes, yet water has received little consideration for its role in possibly modulating immune functions. We examined the relationship between immunocompetence and hydration state using the western diamond-backed rattlesnake (Crotalus atrox). This species is known to undergo substantial seasonal fluctuations in water availability with extreme limitations during the hot, dry season. We collected blood samples from free-ranging C. atrox to compare osmolality and innate immune function (lysis, agglutination, bacterial growth inhibition) during the milder and relatively moister early spring season, the hot-dry season, and the hot-wet season. To isolate effects of dehydration from other possible seasonal influences, we complemented this field study with a laboratory study in which we withheld food and water from individually housed adult C. atrox for up to 16 weeks. We collected blood samples from each snake as it dehydrated and collected a final sample after the snake was given ad lib water at the end of the experiment. Our results demonstrate that C. atrox experience significant dehydration during the hot-dry season, and that, in general, innate immune function is highly correlated with osmolality, whether natural or artificially manipulated.

  11. GATA-3 function in innate and adaptive immunity.

    PubMed

    Tindemans, Irma; Serafini, Nicolas; Di Santo, James P; Hendriks, Rudi W

    2014-08-21

    The zinc-finger transcription factor GATA-3 has received much attention as a master regulator of T helper 2 (Th2) cell differentiation, during which it controls interleukin-4 (IL-4), IL-5, and IL-13 expression. More recently, GATA-3 was shown to contribute to type 2 immunity through regulation of group 2 innate lymphoid cell (ILC2) development and function. Furthermore, during thymopoiesis, GATA-3 represses B cell potential in early T cell precursors, activates TCR signaling in pre-T cells, and promotes the CD4(+) T cell lineage after positive selection. GATA-3 also functions outside the thymus in hematopoietic stem cells, regulatory T cells, CD8(+) T cells, thymic natural killer cells, and ILC precursors. Here we discuss the varied functions of GATA-3 in innate and adaptive immune cells, with emphasis on its activity in T cells and ILCs, and examine the mechanistic basis for the dose-dependent, developmental-stage- and cell-lineage-specific activity of this transcription factor.

  12. Mechanisms of Borrelia burgdorferi internalization and intracellular innate immune signaling.

    PubMed

    Petnicki-Ocwieja, Tanja; Kern, Aurelie

    2014-01-01

    Lyme disease is a long-term infection whose most severe pathology is characterized by inflammatory arthritis of the lower bearing joints, carditis, and neuropathy. The inflammatory cascades are initiated through the early recognition of invading Borrelia burgdorferi spirochetes by cells of the innate immune response, such as neutrophils and macrophage. B. burgdorferi does not have an intracellular niche and thus much research has focused on immune pathways activated by pathogen recognition molecules at the cell surface, such as the Toll-like receptors (TLRs). However, in recent years, studies have shown that internalization of the bacterium by host cells is an important component of the defense machinery in response to B. burgdorferi. Upon internalization, B. burgdorferi is trafficked through an endo/lysosomal pathway resulting in the activation of a number of intracellular pathogen recognition receptors including TLRs and Nod-like receptors (NLRs). Here we will review the innate immune molecules that participate in both cell surface and intracellular immune activation by B. burgdorferi.

  13. Adrenergic regulation of innate immunity: a review

    PubMed Central

    Scanzano, Angela; Cosentino, Marco

    2015-01-01

    The sympathetic nervous system has a major role in the brain-immune cross-talk, but few information exist on the sympathoadrenergic regulation of innate immune system. The aim of this review is to summarize available knowledge regarding the sympathetic modulation of the innate immune response, providing a rational background for the possible repurposing of adrenergic drugs as immunomodulating agents. The cells of immune system express adrenoceptors (AR), which represent the target for noradrenaline and adrenaline. In human neutrophils, adrenaline and noradrenaline inhibit migration, CD11b/CD18 expression, and oxidative metabolism, possibly through β-AR, although the role of α1- and α2-AR requires further investigation. Natural Killer express β-AR, which are usually inhibitory. Monocytes express β-AR and their activation is usually antiinflammatory. On murine Dentritic cells (DC), β-AR mediate sympathetic influence on DC-T cells interactions. In human DC β2-AR may affect Th1/2 differentiation of CD4+ T cells. In microglia and in astrocytes, β2-AR dysregulation may contribute to neuroinflammation in autoimmune and neurodegenerative disease. In conclusion, extensive evidence supports a critical role for adrenergic mechanisms in the regulation of innate immunity, in peripheral tissues as well as in the CNS. Sympathoadrenergic pathways in the innate immune system may represent novel antiinflammatory and immunomodulating targets with significant therapeutic potential. PMID:26321956

  14. Rainbow Trout Innate Immunity against Flavobacterium psychrophilum

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Flavobacterium psychrophilum infection is associated with significant loss of rainbow trout production in the U.S. and other parts of the world. In 2005, a selective breeding program was initiated at the National Center for Cool and Cold Water Aquaculture to improve rainbow trout innate resistance ...

  15. Chemokines in Innate and Adaptive Granuloma Formation

    PubMed Central

    Chensue, Stephen W.

    2012-01-01

    Granulomas are cellular inflammations that vary widely in histologic appearance depending upon the inciting agent and immunologic status of the responding host. Despite their heterogeneity, granulomas are at their core an ancient innate sequestration response characterized by the accumulation of mononuclear phagocytes. In fact, this innate cellular response was first observed by Metchnikov in simple invertebrates. Among higher vertebrates, environmental pressures have resulted in the evolution of more sophisticated adaptive immune responses which can be superimposed upon and modify the character of granulomatous inflammation. Compared to immune responses that rapidly neutralize and eliminate infectious agents, the granuloma represents a less desirable “fall back” response which still has value to the host but can be co-opted by certain infectious agents and contribute to bystander organ damage. Understanding granulomas requires an analysis of the complex interplay of innate and adaptive molecular signals that govern the focal accumulation and activity of their cellular components. Among these signals, small molecular weight chemoattractant proteins known as chemokines are potentially important contributors as they participate in both directing leukocyte migration and function. This tract will discuss the contribution of chemokines to the development of innate and adaptive granuloma formation, as well as describe their relationship to more recently evolved cytokines generated during adaptive immune responses. PMID:23444049

  16. The evolution of innate lymphoid cells

    PubMed Central

    Vivier, Eric; van de Pavert, Serge A; Cooper, Max D; Belz, Gabrielle T

    2017-01-01

    Innate lymphoid cells (ILCs) are the most recently discovered group of immune cells. Understanding their biology poses many challenges. We discuss here the current knowledge on the appearance of ILC subsets during evolution and propose how the connection between ILCs and T cells contributes to the robustness of immunity and hence to the fitness of the hosts. PMID:27328009

  17. Conservation Laws

    NASA Astrophysics Data System (ADS)

    Dewitt, Bryce; Christensen, Steven M.

    In the case of the free particle, we interpreted various components of the energy-momentum-stress density as fluxes of energy and momentum. This interpretation can obviously be extended also to particle ensembles and gases. When we speak of fluxes we usually think of quantities that are conserved. In special relativity, energy and momentum are conserved. In general relativity, they are no longer generally conserved, at least if we do not include the energy and momentum of the gravitational field itself. Nevertheless, their densities and fluxes satisfy a covariant generalization of a true conservation law, which is quite easy to obtain.

  18. Collectins and collectin receptors in innate immunity.

    PubMed

    Holmskov, U L

    2000-01-01

    This thesis is based on nine papers and a review on the collectins and collectin receptors in innate immunity. The collectins are a family of proteins in which the individual chains consist of a C-type lectin domain attached to a collagen domain via an alpha-coiled neck region. The chains are organized into a triple collagen helix and oligomerized through N-terminally located cysteines. The collectins have a dual function: one is to bind specifically to carbohydrate structures on the surface of a pathogen; the other is subsequently to recruit other cells and molecules to destroy the pathogen. The C-type lectin domains contain 110-130 amino-acid residues arranged in a conserved sequence pattern which allows the domain to fold into a well-defined tertiary structure. Five collectins have been described. Lung surfactant proteins A and D (SP-A and SP-D) are mainly found in the surfactant coating the luminal surface of the pulmonary epithelial cells, but are also produced by cells lining the gastrointestinal tract. Mannan-binding lectin (MBL), conglutinin and collectin-43 (CL-43) are serum proteins produced by the liver. Conglutinin and CL-43 have so far only been found in Bovidae. The collectins are involved in innate, nonadaptive immune defense. They bind to microbial surface carbohydrates, inducing aggregation and thereby impeding infectivity or mediating phagocytosis through specific receptors on the phagocytes. After binding microbial carbohydrate, MBL can activate the complement system through a newly discovered pathway which makes use of two serine proteases (MASP-1 and MASP-2) to activate the complement factors C4 and C2. In man, low serum MBL concentrations resulting from mutations in the collagen region are associated with a common opsonic defect. CL-43 was identified as a new collectin by its calcium-dependent binding to mannan and by its M(r) of 43 kDa in the reduced state on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The lectin was

  19. Developing a Sight Conservation Program

    ERIC Educational Resources Information Center

    Braxton, Olivia A.; Farris, R. Linsy

    1975-01-01

    Among the services added to Harlem (New York) Hospital's opthalmology department was a sight conservation program designed to alert the community to the need for eye care and to screen for early signs of eye disorders causing sight impairment. (SB)

  20. miR-34 Modulates Innate Immunity and Ecdysone Signaling in Drosophila

    PubMed Central

    Xiong, Xiao-Peng; Chang, Kung-Yen; Ren, Xingjie; Ni, Jian-Quan; Rana, Tariq M.; Zhou, Rui

    2016-01-01

    microRNAs are endogenous small regulatory RNAs that modulate myriad biological processes by repressing target gene expression in a sequence-specific manner. Here we show that the conserved miRNA miR-34 regulates innate immunity and ecdysone signaling in Drosophila. miR-34 over-expression activates antibacterial innate immunity signaling both in cultured cells and in vivo, and flies over-expressing miR-34 display improved survival and pathogen clearance upon Gram-negative bacterial infection; whereas miR-34 knockout animals are defective in antibacterial defense. In particular, miR-34 achieves its immune-stimulatory function, at least in part, by repressing the two novel target genes Dlg1 and Eip75B. In addition, our study reveals a mutual repression between miR-34 expression and ecdysone signaling, and identifies miR-34 as a node in the intricate interplay between ecdysone signaling and innate immunity. Lastly, we identify cis-regulatory genomic elements and trans-acting transcription factors required for optimal ecdysone-mediated repression of miR-34. Taken together, our study enriches the repertoire of immune-modulating miRNAs in animals, and provides new insights into the interplay between steroid hormone signaling and innate immunity. PMID:27893816

  1. Are the innate and adaptive immune systems setting hypertension on fire?

    PubMed

    Bomfim, Gisele F; Rodrigues, Fernanda Luciano; Carneiro, Fernando S

    2017-03-01

    Hypertension is the most common chronic cardiovascular disease and is associated with several pathological states, being an important cause of morbidity and mortality around the world. Low-grade inflammation plays a key role in hypertension and the innate and adaptive immune systems seem to contribute to hypertension development and maintenance. Hypertension is associated with vascular inflammation, increased vascular cytokines levels and infiltration of immune cells in the vasculature, kidneys and heart. However, the mechanisms that trigger inflammation and immune system activation in hypertension are completely unknown. Cells from the innate immune system express pattern recognition receptors (PRR), which detect conserved pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) that induce innate effector mechanisms to produce endogenous signals, such as inflammatory cytokines and chemokines, to alert the host about danger. Additionally, antigen-presenting cells (APC) act as sentinels that are activated by PAMPs and DAMPs to sense the presence of the antigen/neoantigen, which ensues the adaptive immune system activation. In this context, different lymphocyte types are activated and contribute to inflammation and end-organ damage in hypertension. This review will focus on experimental and clinical evidence demonstrating the contribution of the innate and adaptive immune systems to the development of hypertension.

  2. miR-34 Modulates Innate Immunity and Ecdysone Signaling in Drosophila.

    PubMed

    Xiong, Xiao-Peng; Kurthkoti, Krishna; Chang, Kung-Yen; Li, Jian-Liang; Ren, Xingjie; Ni, Jian-Quan; Rana, Tariq M; Zhou, Rui

    2016-11-01

    microRNAs are endogenous small regulatory RNAs that modulate myriad biological processes by repressing target gene expression in a sequence-specific manner. Here we show that the conserved miRNA miR-34 regulates innate immunity and ecdysone signaling in Drosophila. miR-34 over-expression activates antibacterial innate immunity signaling both in cultured cells and in vivo, and flies over-expressing miR-34 display improved survival and pathogen clearance upon Gram-negative bacterial infection; whereas miR-34 knockout animals are defective in antibacterial defense. In particular, miR-34 achieves its immune-stimulatory function, at least in part, by repressing the two novel target genes Dlg1 and Eip75B. In addition, our study reveals a mutual repression between miR-34 expression and ecdysone signaling, and identifies miR-34 as a node in the intricate interplay between ecdysone signaling and innate immunity. Lastly, we identify cis-regulatory genomic elements and trans-acting transcription factors required for optimal ecdysone-mediated repression of miR-34. Taken together, our study enriches the repertoire of immune-modulating miRNAs in animals, and provides new insights into the interplay between steroid hormone signaling and innate immunity.

  3. The interaction between maternal stress and the ontogeny of the innate immune system during teleost embryogenesis: implications for aquaculture practice.

    PubMed

    Li, M; Leatherland, J F

    2012-11-01

    The barrier defences and acellular innate immune proteins play critical roles during the early-stage fish embryos prior to the development of functional organ systems. The innate immune proteins in the yolk of embryos are of maternal origin. Maternal stress affects the maternal-to-embryo transfer of these proteins and, therefore, environmental stressors may change the course of embryo development, including embryonic immunocompetency, via their deleterious effect on maternal physiology. This review focuses on the associations that exist between maternal stress, maternal endocrine disturbance and the responses of the acellular innate immune proteins of early-stage fish embryos. Early-stage teleostean embryos are dependent upon the adult female for the formation of the zona pellucida as an essential barrier defence, for their supply of nutrients, and for the innate immunity proteins and antibodies that are transferred from the maternal circulation to the oocytes; maternally derived hormones are also transferred, some of which (such as cortisol) are known to exert a suppressive action on some aspects of the immune defences. This review summarizes what is known about the effects of oocyte cortisol content on the immune system components in early embryos. The review also examines recent evidence that embryonic cells during early cleavage have the capacity to respond to increased maternal cortisol transfer; this emphasizes the importance of maternal and early immune competence on the later life of fishes, both in the wild and in intensive culture.

  4. [Innate immunity: cutaneous expression of Toll-like receptors].

    PubMed

    Musette, Philippe; Auquit Auckbur, Isabelle; Begon, Edouard

    2006-02-01

    Toll receptors were first identified as an essential molecule for embryonic patterning in Drosophila and were subsequently shown to be a key in antibacterial and antifungal immunity in adult flies. Toll receptors have been conserved throughout evolution. In mammals, TLRs have been implicated in both inflammatory responses and innate host defense to pathogens. The 11 different TLRs recognize conserved molecular patterns of microbial pathogens termed pathogen-specific molecular patterns (PAMPs), that permit to confer responsiveness to a wide variety of pathogens. Endogenous ligands are also able to activate TLRs. All adult tissue is capable to express at least one of member of TLR family, but a largest repertoire of TLRs is found in tissues exposed to the external environment. The TLR activation induce the NF-kappaB translocation to the nucleus and cytokine secretion. Since the primary function of skin is to provide an effective barrier against outside agression, it is likely that keratinocytes may play a role in a rapid and efficient host defence system, and the fact that keratinocytes are capable of expressing a wide variety of TLRs is subsequently not surprising.

  5. Conservation Tillage

    NASA Astrophysics Data System (ADS)

    Gebhardt, Maurice R.; Daniel, Tommy C.; Schweizer, Edward E.; Allmaras, Raymond R.

    1985-11-01

    Conservation production systems combine tillage and planting practices to reduce soil erosion and loss of water from farmland. Successful conservation tillage practices depend on the ability of farm managers to integrate sound crop production practices with effective pest management systems. More scientific information is needed to determine the relations between tillage practices and physical, chemical, and biological soil factors that affect plant and pest ecology. There is a need to devise improved pest management strategies for conservation tillage and to better understand the impact of conservation tillage on water quality, especially as it is related to use of agricultural chemicals. While savings in fuel, labor, and soil have induced many farmers to adopt conservation tillage, improved methods and equipment should increase adoption even more.

  6. Viral evasion of DNA-stimulated innate immune responses

    PubMed Central

    Christensen, Maria H; Paludan, Søren R

    2017-01-01

    Cellular sensing of virus-derived nucleic acids is essential for early defenses against virus infections. In recent years, the discovery of DNA sensing proteins, including cyclic GMP–AMP synthase (cGAS) and gamma-interferon-inducible protein (IFI16), has led to understanding of how cells evoke strong innate immune responses against incoming pathogens carrying DNA genomes. The signaling stimulated by DNA sensors depends on the adaptor protein STING (stimulator of interferon genes), to enable expression of antiviral proteins, including type I interferon. To facilitate efficient infections, viruses have evolved a wide range of evasion strategies, targeting host DNA sensors, adaptor proteins and transcription factors. In this review, the current literature on virus-induced activation of the STING pathway is presented and we discuss recently identified viral evasion mechanisms targeting different steps in this antiviral pathway. PMID:26972769

  7. Phylogeny of Toll-Like Receptor Signaling: Adapting the Innate Response

    PubMed Central

    Roach, Jeffrey M.; Racioppi, Luigi; Jones, Corbin D.; Masci, Anna Maria

    2013-01-01

    The Toll-like receptors represent a largely evolutionarily conserved pathogen recognition machinery responsible for recognition of bacterial, fungal, protozoan, and viral pathogen associated microbial patterns and initiation of inflammatory response. Structurally the Toll-like receptors are comprised of an extracellular leucine rich repeat domain and a cytoplasmic Toll/Interleukin 1 receptor domain. Recognition takes place in the extracellular domain where as the cytoplasmic domain triggers a complex signal network required to sustain appropriate immune response. Signal transduction is regulated by the recruitment of different intracellular adaptors. The Toll-like receptors can be grouped depending on the usage of the adaptor, MyD88, into MyD88-dependent and MyD88 independent subsets. Herein, we present a unique phylogenetic analysis of domain regions of these receptors and their cognate signaling adaptor molecules. Although previously unclear from the phylogeny of full length receptors, these analyses indicate a separate evolutionary origin for the MyD88-dependent and MyD88-independent signaling pathway and provide evidence of a common ancestor for the vertebrate and invertebrate orthologs of the adaptor molecule MyD88. Together these observations suggest a very ancient origin of the MyD88-dependent pathway Additionally we show that early duplications gave rise to several adaptor molecule families. In some cases there is also strong pattern of parallel duplication between adaptor molecules and their corresponding TLR. Our results further support the hypothesis that phylogeny of specific domains involved in signaling pathway can shed light on key processes that link innate to adaptive immune response. PMID:23326591

  8. Oxidative stress, innate immunity, and age-related macular degeneration.

    PubMed

    Shaw, Peter X; Stiles, Travis; Douglas, Christopher; Ho, Daisy; Fan, Wei; Du, Hongjun; Xiao, Xu

    Age-related macular degeneration (AMD) is a leading cause of vision loss affecting tens of millions of elderly worldwide. Early AMD is characterized by the appearance of soft drusen, as well as pigmentary changes in the retinal pigment epithelium (RPE). These soft, confluent drusen can progress into two forms of advanced AMD: geographic atrophy (GA, or dry AMD) or choroidal neovascularization (CNV, or wet AMD). Both forms of AMD result in a similar clinical progression in terms of loss of central vision. The exact mechanism for developing early AMD, as well as triggers responsible for progressing to advanced stage of disease, is still largely unknown. However, significant evidence exists demonstrating a complex interplay of genetic and environmental factors as causes of AMD progression. Multiple genes and/or single nucleotide polymorphisms (SNPs) have been found associated with AMD, including various genes involved in the complement pathway, lipid metabolism and extracellular matrix (ECM) remodeling. Of the known genetic contributors to disease risk, the CFH Y402H and HTRA1/ARMS polymorphisms contribute to more than 50% of the genetic risk for AMD. Environmentally, oxidative stress plays a critical role in many aging diseases including cardiovascular disease, cancer, Alzheimer's disease and AMD. Due to the exposure to sunlight and high oxygen concentration, the oxidative stress burden is higher in the eye than other tissues, which can be further complicated by additional oxidative stressors such as smoking. Increasingly, evidence is accumulating suggesting that functional abnormalities of the innate immune system incurred via high risk genotypes may be contributing to the pathogenesis of AMD by altering the inflammatory homeostasis in the eye, specifically in the handling of oxidation products. As the eye in non-pathological instances maintains a low level of inflammation despite the presence of a relative abundance of potentially inflammatory molecules, we have

  9. Oxidative stress, innate immunity, and age-related macular degeneration

    PubMed Central

    Shaw, Peter X.; Stiles, Travis; Douglas, Christopher; Ho, Daisy; Fan, Wei; Du, Hongjun; Xiao, Xu

    2016-01-01

    Age-related macular degeneration (AMD) is a leading cause of vision loss affecting tens of millions of elderly worldwide. Early AMD is characterized by the appearance of soft drusen, as well as pigmentary changes in the retinal pigment epithelium (RPE). These soft, confluent drusen can progress into two forms of advanced AMD: geographic atrophy (GA, or dry AMD) or choroidal neovascularization (CNV, or wet AMD). Both forms of AMD result in a similar clinical progression in terms of loss of central vision. The exact mechanism for developing early AMD, as well as triggers responsible for progressing to advanced stage of disease, is still largely unknown. However, significant evidence exists demonstrating a complex interplay of genetic and environmental factors as causes of AMD progression. Multiple genes and/or single nucleotide polymorphisms (SNPs) have been found associated with AMD, including various genes involved in the complement pathway, lipid metabolism and extracellular matrix (ECM) remodeling. Of the known genetic contributors to disease risk, the CFH Y402H and HTRA1/ARMS polymorphisms contribute to more than 50% of the genetic risk for AMD. Environmentally, oxidative stress plays a critical role in many aging diseases including cardiovascular disease, cancer, Alzheimer’s disease and AMD. Due to the exposure to sunlight and high oxygen concentration, the oxidative stress burden is higher in the eye than other tissues, which can be further complicated by additional oxidative stressors such as smoking. Increasingly, evidence is accumulating suggesting that functional abnormalities of the innate immune system incurred via high risk genotypes may be contributing to the pathogenesis of AMD by altering the inflammatory homeostasis in the eye, specifically in the handling of oxidation products. As the eye in non-pathological instances maintains a low level of inflammation despite the presence of a relative abundance of potentially inflammatory molecules, we have

  10. Salt, chloride, bleach, and innate host defense

    PubMed Central

    Wang, Guoshun; Nauseef, William M.

    2015-01-01

    Salt provides 2 life-essential elements: sodium and chlorine. Chloride, the ionic form of chlorine, derived exclusively from dietary absorption and constituting the most abundant anion in the human body, plays critical roles in many vital physiologic functions, from fluid retention and secretion to osmotic maintenance and pH balance. However, an often overlooked role of chloride is its function in innate host defense against infection. Chloride serves as a substrate for the generation of the potent microbicide chlorine bleach by stimulated neutrophils and also contributes to regulation of ionic homeostasis for optimal antimicrobial activity within phagosomes. An inadequate supply of chloride to phagocytes and their phagosomes, such as in CF disease and other chloride channel disorders, severely compromises host defense against infection. We provide an overview of the roles that chloride plays in normal innate immunity, highlighting specific links between defective chloride channel function and failures in host defense. PMID:26048979

  11. Neutrophils: Cinderella of innate immune system.

    PubMed

    Kumar, V; Sharma, A

    2010-11-01

    Neutrophils are the first line of innate immune defense against infectious diseases. However, since their discovery by Elie Metchnikoff, they have always been considered tissue-destructive cells responsible for inflammatory tissue damage occurring during acute infections. Now, extensive research in the field of neutrophil cell biology and their role skewing the immune response in various infections or inflammatory disorders revealed their importance in the regulation of immune response. Along with releasing various antimicrobial molecules, neutrophils also release neutrophil extracellular traps (NETs) for the containment of infection and inflammation. Activated neutrophils provide signals for the activation and maturation of macrophages as well as dendritic cells. Neutrophils are also involved in the regulation of T-cell immune response against various pathogens and tumor antigens. Thus, the present review is intended to highlight the emerging role of neutrophils in the regulation of both innate and adaptive immunity during acute infectious or inflammatory conditions.

  12. The innate immune system and transplantation.

    PubMed

    Farrar, Conrad A; Kupiec-Weglinski, Jerzy W; Sacks, Steven H

    2013-10-01

    The sensitive and broadly reactive character of the innate immune system makes it liable to activation by stress factors other than infection. Thermal and metabolic stresses experienced during the transplantation procedure are sufficient to trigger the innate immune response and also augment adaptive immunity in the presence of foreign antigen on the donor organ. The resulting inflammatory and immune reactions combine to form a potent effector response that can lead to graft rejection. Here we examine the evidence that the complement and toll-like receptor systems are central to these pathways of injury and present a formidable barrier to transplantation. We review extensive information about the effector mechanisms that are mediated by these pathways, and bring together what is known about the damage-associated molecular patterns that initiate this sequence of events. Finally, we refer to two ongoing therapeutic trials that are evaluating the validity of these concepts in man.

  13. CNS Remyelination and the Innate Immune System

    PubMed Central

    McMurran, Christopher E.; Jones, Clare A.; Fitzgerald, Denise C.; Franklin, Robin J. M.

    2016-01-01

    A misguided inflammatory response is frequently implicated in myelin damage. Particularly prominent among myelin diseases, multiple sclerosis (MS) is an autoimmune condition, with immune–mediated damage central to its etiology. Nevertheless, a robust inflammatory response is also essential for the efficient regeneration of myelin sheaths after such injury. Here, we discuss the functions of inflammation that promote remyelination, and how these have been experimentally disentangled from the pathological facets of the immune response. We focus on the contributions that resident microglia and monocyte-derived macrophages make to remyelination and compare the roles of these two populations of innate immune cells. Finally, the current literature is framed in the context of developing therapies that manipulate the innate immune response to promote remyelination in clinical myelin disease. PMID:27200350

  14. Salt, chloride, bleach, and innate host defense.

    PubMed

    Wang, Guoshun; Nauseef, William M

    2015-08-01

    Salt provides 2 life-essential elements: sodium and chlorine. Chloride, the ionic form of chlorine, derived exclusively from dietary absorption and constituting the most abundant anion in the human body, plays critical roles in many vital physiologic functions, from fluid retention and secretion to osmotic maintenance and pH balance. However, an often overlooked role of chloride is its function in innate host defense against infection. Chloride serves as a substrate for the generation of the potent microbicide chlorine bleach by stimulated neutrophils and also contributes to regulation of ionic homeostasis for optimal antimicrobial activity within phagosomes. An inadequate supply of chloride to phagocytes and their phagosomes, such as in CF disease and other chloride channel disorders, severely compromises host defense against infection. We provide an overview of the roles that chloride plays in normal innate immunity, highlighting specific links between defective chloride channel function and failures in host defense.

  15. Innate lymphoid cells in inflammation and immunity.

    PubMed

    McKenzie, Andrew N J; Spits, Hergen; Eberl, Gerard

    2014-09-18

    Innate lymphoid cells (ILCs) were first described as playing important roles in the development of lymphoid tissues and more recently in the initiation of inflammation at barrier surfaces in response to infection or tissue damage. It has now become apparent that ILCs play more complex roles throughout the duration of immune responses, participating in the transition from innate to adaptive immunity and contributing to chronic inflammation. The proximity of ILCs to epithelial surfaces and their constitutive strategic positioning in other tissues throughout the body ensures that, in spite of their rarity, ILCs are able to regulate immune homeostasis effectively. Dysregulation of ILC function might result in chronic pathologies such as allergies, autoimmunity, and inflammation. A new role for ILCs in the maintenance of metabolic homeostasis has started to emerge, underlining their importance in fundamental physiological processes beyond infection and immunity.

  16. Innate and Adaptive Immunity in Atherosclerosis

    PubMed Central

    Packard, René R. S.; Lichtman, Andrew H.; Libby, Peter

    2010-01-01

    Atherosclerosis, a chronic inflammatory disorder, involves both the innate and adaptive arms of the immune response that mediate the initiation, progression, and ultimate thrombotic complications of atherosclerosis. Most fatal thromboses, which may manifest as acute myocardial infarction or ischemic stroke, result from frank rupture or superficial erosion of the fibrous cap overlying the atheroma, processes that occur in inflammatorily active, rupture-prone plaques. Appreciation of the inflammatory character of atherosclerosis has led to the application of C-reactive protein as a biomarker of cardiovascular risk, and the characterization of the anti-inflammatory and immunomodulatory actions of the statin class of drugs. An improved understanding of the pathobiology of atherosclerosis and further studies of its immune mechanisms provide avenues for the development of future strategies directed toward better risk stratification of patients as well as the identification of novel anti-inflammatory therapies. This review retraces leukocyte subsets involved in innate and adaptive immunity and their contributions to atherogenesis. PMID:19449008

  17. In this issue: autoimmunity and innate immunity.

    PubMed

    Bot, Adrian

    2014-01-01

    In this issue of the journal, we host a range of topics relevant to innate immunity as well as certain inflammatory diseases. More specifically, Sanz et al. cover a tantalizing form of death called pyroptosis that leads to inflammation. Samasca et al. provide a brief perspective on celiac disease. Singh and collaborators discuss in detail a newly designed leptin antagonist that could be applicable to colitis treatment. Through a meta-analysis, Wen et al. show that IL-18 gene polymorphism is associated with RA and SLE. Adenovirus-triggered innate immunity is discussed by Chen and Lee. Further, Zheng et al. provide a review of lectin receptors and their importance to anti-microbial immunity. Finally, Rojas et al. discuss tantalizing evidence supporting the fact that endogenous danger motifs such as advanced glycation end products are recognized via a TLR-like molecule and signaling pathway.

  18. Early functional, esthetic, and psychological rehabilitation of preschool child with nonsyndromic oligodontia and anodontia in mixed dentition stage through conservative systematic approach: A case report with 5-year follow-up

    PubMed Central

    Rathee, Manu; Malik, Poonam; Dua, Madhuri; Yadav, Vikas

    2016-01-01

    Missing teeth are a common developmental abnormality in humans. It may manifest as absence of varying numbers of primary and/or secondary teeth. Early treatment and follow-up are the key to successful rehabilitation of young patients with congenitally missing teeth. It is critical that oral rehabilitation is started early to maintain and correct the oral functions. Mucosa borne removable prostheses are the commonly selected treatment options for the young patients who present with oligodontia or anodontia. This clinical report describes esthetic, functional, and psychological rehabilitation of a young boy with severe oligodontia in maxillary arch and anodontia in mandibular arch. The individualized conservative graded approach in prosthetic rehabilitation with removable acrylic prosthesis helped to achieve esthetics, functionality, and psychological benefits. PMID:27307674

  19. Oral innate immunity in HIV infection in HAART era.

    PubMed

    Nittayananta, Wipawee; Tao, Renchuan; Jiang, Lanlan; Peng, Yuanyuan; Huang, Yuxiao

    2016-01-01

    Oral innate immunity, an important component in host defense and immune surveillance in the oral cavity, plays a crucial role in the regulation of oral health. As part of the innate immune system, epithelial cells lining oral mucosal surfaces not only provide a physical barrier but also produce different antimicrobial peptides, including human β-defensins (hBDs), secretory leukocyte protease inhibitor (SLPI), and various cytokines. These innate immune mediators help in maintaining oral homeostasis. When they are impaired either by local or systemic causes, various oral infections and malignancies may be developed. Human immunodeficiency virus (HIV) infection and other co-infections appear to have both direct and indirect effects on systemic and local innate immunity leading to the development of oral opportunistic infections and malignancies. Highly active antiretroviral therapy (HAART), the standard treatment of HIV infection, contributed to a global reduction of HIV-associated oral lesions. However, prolonged use of HAART may lead to adverse effects on the oral innate immunity resulting in the relapse of oral lesions. This review article focused on the roles of oral innate immunity in HIV infection in HAART era. The following five key questions were addressed: (i) What are the roles of oral innate immunity in health and disease?, (ii) What are the effects of HIV infection on oral innate immunity?, (iii) What are the roles of oral innate immunity against other co-infections?, (iv) What are the effects of HAART on oral innate immunity?, and (v) Is oral innate immunity enhanced by HAART?

  20. Rosetta Stone of NLR Innate Immunity.

    PubMed

    Lechtenberg, Bernhard C; Riedl, Stefan J

    2016-01-01

    The formation of NLR inflammasomes is a central step in the initiation of the innate immune response. Two recent publications describe the structure of the NAIP2-NLRC4 inflammasome and derive an elegant model of NLR inflammasome formation, whereby binding of the pathogen-molecule-bound NLR NAIP2 to NLRC4 leads to the activation of NLRC4 and initiation of self-propagating NLRC4 inflammasome formation.

  1. Innate immunity and primary biliary cirrhosis.

    PubMed

    Selmi, Carlo; Lleo, Ana; Pasini, Simone; Zuin, Massimo; Gershwin, M Eric

    2009-02-01

    There has been a rapid growth in our understanding of the molecular bases of primary biliary cirrhosis (PBC). These efforts were initiated when the immunodominant mitochondrial autoantigen was cloned and sequenced. Using the recombinant cloned antigen as a tool, research has focused on the effector mechanisms of disease and the uniqueness of the primary target tissue, the intrahepatic bile ducts. Most recently, there have been experimental data suggesting that innate immunity changes may be critical to the initiation and perpetuation of the autoimmune injury, as in the case of the enhanced response of monocytes and memory B cells to infectious stimulation and environmental mimics. These observations are important as they help fill in the many gaps which remain on the most difficult subject of autoimmunity, etiology. Indeed, based on the available data, several experimental models of PBC have been developed. These models illustrate and suggest that PBC can be initiated by several mechanisms, all of which lead to loss of tolerance to the mitochondrial antigens. However, once this adaptive response develops, it appears that much of the subsequent pathology is exacerbated by innate responses. We suggest that future therapeutic efforts in PBC will depend heavily on understanding the nature of this innate immune responses and methodology to blunt their cytotoxicity.

  2. The Innate Immune Response Against Staphylococcus aureus.

    PubMed

    Bekeredjian-Ding, Isabelle; Stein, Christoph; Uebele, Julia

    2015-12-15

    The innate immune system harbors a multitude of different receptor systems and cells that are constantly prepared to sense and eliminate invading microbial pathogens. Staphylococcus aureus enters the body on its exposed epithelial surfaces, e.g., on skin and mucosa. The initial interaction with epithelial cells is governed by Toll-like receptor (TLR)-2-mediated local production of soluble mediators, including cytokines, chemokines, and antimicrobial peptides. The overall goal is to achieve a steady state of immune mediators and colonizing bacteria. Following cell and tissue invasion clearance of bacteria depends on intracellular microbial sensors and subsequent activation of the inflammasomes. Tissue-resident mast cells and macrophages recruit neutrophils, macrophages, and NK cells. This inflammatory response supports the generation of IL-17 producing NKT, γδ T cells, and T helper cells. Local dendritic cells migrate to the lymph nodes and fine-tune the adaptive immune response. The scope of this chapter is to provide an overview on the major cell types and receptors involved in innate immune defense against S. aureus. By segregating the different stages of infection from epithelial barrier to intracellular and systemic infection, this chapter highlights the different qualities of the innate immune response to S. aureus at different stages of invasiveness.

  3. Innate immune dysfunction in inflammatory bowel disease.

    PubMed

    Gersemann, M; Wehkamp, J; Stange, E F

    2012-05-01

    The pathogenetic mechanisms that cause the two types of inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC), are still under investigation. Nevertheless, there is broad agreement that luminal microbes are of particular relevance in the development of these conditions. In recent years, increasing evidence has shown that defects in the innate immunity are at the centre of both types of IBD. The innate intestinal barrier is provided by the epithelium which secretes antimicrobial peptides (so-called defensins) that are retained in the mucus layer. In ileal CD, the alpha-defensins are lacking owing to several Paneth cell defects. In colonic CD, the expression of beta-defensins is inadequate. This may be related to downregulation of the transcription factor peroxisome proliferator-activated receptor-gamma and in some cohorts is associated with a reduced HBD2 gene copy number. In UC, the mucus layer, which protects the host from the enormous amounts of luminal microbes, is defective. This is accompanied by an insufficient differentiation from intestinal stem cells towards goblet cells. All these disturbances in the gut barrier shift the balance from epithelial defence towards bacterial offence. The current treatment for CD and UC is based on suppression of this secondary inflammatory process. In future, patients may benefit from new therapeutic approaches stimulating the protective innate immune system.

  4. Prion Disease and the Innate Immune System

    PubMed Central

    Bradford, Barry M.; Mabbott, Neil A.

    2012-01-01

    Prion diseases or transmissible spongiform encephalopathies are a unique category of infectious protein-misfolding neurodegenerative disorders. Hypothesized to be caused by misfolding of the cellular prion protein these disorders possess an infectious quality that thrives in immune-competent hosts. While much has been discovered about the routing and critical components involved in the peripheral pathogenesis of these agents there are still many aspects to be discovered. Research into this area has been extensive as it represents a major target for therapeutic intervention within this group of diseases. The main focus of pathological damage in these diseases occurs within the central nervous system. Cells of the innate immune system have been proven to be critical players in the initial pathogenesis of prion disease, and may have a role in the pathological progression of disease. Understanding how prions interact with the host innate immune system may provide us with natural pathways and mechanisms to combat these diseases prior to their neuroinvasive stage. We present here a review of the current knowledge regarding the role of the innate immune system in prion pathogenesis. PMID:23342365

  5. Heme on innate immunity and inflammation

    PubMed Central

    Dutra, Fabianno F.; Bozza, Marcelo T.

    2014-01-01

    Heme is an essential molecule expressed ubiquitously all through our tissues. Heme plays major functions in cellular physiology and metabolism as the prosthetic group of diverse proteins. Once released from cells and from hemeproteins free heme causes oxidative damage and inflammation, thus acting as a prototypic damage-associated molecular pattern. In this context, free heme is a critical component of the pathological process of sterile and infectious hemolytic conditions including malaria, hemolytic anemias, ischemia-reperfusion, and hemorrhage. The plasma scavenger proteins hemopexin and albumin reduce heme toxicity and are responsible for transporting free heme to intracellular compartments where it is catabolized by heme-oxygenase enzymes. Upon hemolysis or severe cellular damage the serum capacity to scavenge heme may saturate and increase free heme to sufficient amounts to cause tissue damage in various organs. The mechanism by which heme causes reactive oxygen generation, activation of cells of the innate immune system and cell death are not fully understood. Although heme can directly promote lipid peroxidation by its iron atom, heme can also induce reactive oxygen species generation and production of inflammatory mediators through the activation of selective signaling pathways. Heme activates innate immune cells such as macrophages and neutrophils through activation of innate immune receptors. The importance of these events has been demonstrated in infectious and non-infectious diseases models. In this review, we will discuss the mechanisms behind heme-induced cytotoxicity and inflammation and the consequences of these events on different tissues and diseases. PMID:24904418

  6. Innate immune responses to hepatitis C virus.

    PubMed

    Schoggins, John W; Rice, Charles M

    2013-01-01

    The innate immune response provides the first line of defense against invading viral pathogens. Incoming viruses are sensed by dedicated host factors that, when triggered, initiate multiple signal transduction pathways. Activation of these pathways leads to the induction of highly orchestrated transcriptional programs designed to limit virus replication and spread. In recent years, our understanding of innate immune responses targeting hepatitis C virus (HCV) has increased substantially, largely due to the development of new systems and methodologies to study HCV-host interactions in vitro and in vivo. However, significant gaps still remain. Here, we aim to provide a comprehensive view of the innate immune response to HCV, focusing primarily on knowledge gained from cell culture models of HCV infection, as well as data from human patients infected with HCV. While some paradigms of the host response to HCV revealed in cell culture translate to human infection in vivo, others are less clear. Further insight into the similarities and differences in these systems will not only reveal directions for future studies on HCV immunity, but may also guide the development of novel strategies to control HCV and other viral infections.

  7. Capping Protein Modulates Actin Remodeling in Response to Reactive Oxygen Species during Plant Innate Immunity1[OPEN

    PubMed Central

    Cao, Lingyan

    2017-01-01

    Plants perceive microbe-associated molecular patterns and damage-associated molecular patterns to activate innate immune signaling events, such as bursts of reactive oxygen species (ROS). The actin cytoskeleton remodels during the first 5 min of innate immune signaling in Arabidopsis (Arabidopsis thaliana) epidermal cells; however, the immune signals that impinge on actin cytoskeleton and its response regulators remain largely unknown. Here, we demonstrate that rapid actin remodeling upon elicitation with diverse microbe-associated molecular patterns and damage-associated molecular patterns represent a conserved plant immune response. Actin remodeling requires ROS generated by the defense-associated NADPH oxidase, RBOHD. Moreover, perception of flg22 by its cognate receptor complex triggers actin remodeling through the activation of RBOHD-dependent ROS production. Our genetic studies reveal that the ubiquitous heterodimeric capping protein transduces ROS signaling to the actin cytoskeleton during innate immunity. Additionally, we uncover a negative feedback loop between actin remodeling and flg22-induced ROS production. PMID:27909046

  8. Energy Conservation

    ERIC Educational Resources Information Center

    Abelson, Philip H.

    1972-01-01

    Comments on The Potential for Energy Conservation,'' a study by the Office of Emergency Preparedness, emphasizing the coming dependence on foreign oil, and presses for government influence to encourage development of more efficient cars. (AL)

  9. Conservation Presentation.

    ERIC Educational Resources Information Center

    Friday, Gerald

    2001-01-01

    Introduces a project in which students teach about the importance of recycling and conservation by presenting demonstrations. Includes demonstrations on water, plastic, and other recycling products such as steel. (YDS)

  10. Serum Lipoproteins are Critical for Pulmonary Innate Defense against Staphylococcus aureus Quorum Sensing

    PubMed Central

    Manifold-Wheeler, Brett C.; Elmore, Bradley O.; Triplett, Kathleen D.; Castleman, Moriah J.; Otto, Michael; Hall, Pamela R.

    2015-01-01

    Hyperlipidemia has been extensively studied in the context of atherosclerosis, whereas the potential health consequences of the opposite extreme, hypolipidemia, remain largely uninvestigated. Circulating lipoproteins are essential carriers of insoluble lipid molecules and are increasingly recognized as innate immune effectors. Importantly, severe hypolipidemia, which may occur with trauma or critical illness, is clinically associated with bacterial pneumonia. To test the hypothesis that circulating lipoproteins are essential for optimal host innate defense in the lung, we used lipoprotein deficient mice and a mouse model of Staphylococcus aureus pneumonia in which invasive infection requires virulence factor expression controlled by the accessory gene regulator (agr) operon. Activation of agr and subsequent virulence factor expression is inhibited by apolipoprotein B, the structural protein of low density lipoprotein, which binds and sequesters the secreted agr-signaling peptide (AIP). Here we report that lipoprotein deficiency impairs early pulmonary innate defense against S. aureus quorum-sensing dependent pathogenesis. Specifically, apoB levels in the lung early post-infection are significantly reduced with lipoprotein deficiency, coinciding with impaired host control of S. aureus agr-signaling and increased agr-dependent morbidity (weight loss) and inflammation. Given that lipoproteins also inhibit LTA- and LPS-mediated inflammation, these results suggest that hypolipidemia may broadly impact post-trauma pneumonia susceptibility to both Gram positive and Gram negative pathogens. Together with previous reports demonstrating that hyperlipidemia also impairs lung innate defense, these results suggest that maintenance of normal serum lipoprotein levels is necessary for optimal host innate defense in the lung. PMID:26608923

  11. Virus-cell fusion as a trigger of innate immunity dependent on the adaptor STING

    PubMed Central

    Holm, Christian K; Jensen, Søren B; Jakobsen, Martin R; Cheshenko, Natalia; Horan, Kristy A; Moeller, Hanne B; Gonzalez-Dosal, Regina; Rasmussen, Simon B; Christensen, Maria H.; Yarovinsky, Timur O; Rixon, Frazer J; Herold, Betsy C; Fitzgerald, Katherine A; Paludan, Søren R

    2012-01-01

    The innate immune system senses infection by detecting evolutionarily conserved molecules essential for microbial survival or abnormal location of molecules. Here we demonstrate the existence of a novel innate detection mechanism, which is induced by fusion between viral envelopes and target cells. Virus-cell fusion specifically stimulated a type I interferon (IFN) response with expression of IFN-stimulated genes (ISGs), in vivo recruitment of leukocytes, and potentiation of Toll-like receptor 7 and 9 signaling. The fusion dependent response was dependent on stimulator of interferon genes (STING) but independent of DNA, RNA and viral capsid. We suggest that membrane fusion is sensed as a danger signal with potential implications for defense against enveloped viruses and various conditions of giant cell formation. PMID:22706339

  12. Toward immunogenetic studies of amphibian chytridiomycosis: Linking innate and acquired immunity

    USGS Publications Warehouse

    Richmond, J.Q.; Savage, Anna E.; Zamudio, Kelly R.; Rosenblum, E.B.

    2009-01-01

    Recent declines in amphibian diversity and abundance have contributed significantly to the global loss of biodiversity. The fungal disease chytridiomycosis is widely considered to be a primary cause of these declines, yet the critical question of why amphibian species differ in susceptibility remains unanswered. Considerable evidence links environmental conditions and interspecific variability of the innate immune system to differential infection responses, but other sources of individual, population, or species-typical variation may also be important. In this article we review the preliminary evidence supporting a role for acquired immune defenses against chytridiomycosis, and advocate for targeted investigation of genes controlling acquired responses, as well as those that functionally bridge the innate and acquired immune systems. Immunogenetic data promise to answer key questions about chytridiomycosis susceptibility and host-pathogen coevolution, and will draw much needed attention to the importance of considering evolutionary processes in amphibian conservation management and practice. ?? 2009 by American Institute of Biological Sciences.

  13. Innate immune reactions stimulated by a lipopolysaccharide-like component of the alga Prototheca (strain 289)

    NASA Astrophysics Data System (ADS)

    Bedick, Jon C.; Shnyra, Alex; Stanley, David W.; Pardy, R.

    2001-11-01

    We report on the influence of an LPS-like molecule (aLPS) from the pathogenic alga, Prototheca (strain 289) on insect and murine innate immune reactions. Insect innate reactions to infection include nodule formation, a process of entrapping bacterial cells in aggregates of hemocytes. We recorded eicosanoid-dependent, dose-related nodulation reactions to aLPS in hornworms ( Manduca sexta). The insect reaction was attenuated by pre-incubating the aLPS with polymyxin-B. Conversely, the murine macrophages reacted to challenge with Escherichia coli LPS by secreting cytokines, but did not react to aLPS. We infer that, while highly conserved with respect to intracellular mechanisms of interaction, insect and mammalian immune surveillance systems differ in recognition of LPS molecular types.

  14. Immune Receptors and Co-receptors in Antiviral Innate Immunity in Plants

    PubMed Central

    Gouveia, Bianca C.; Calil, Iara P.; Machado, João Paulo B.; Santos, Anésia A.; Fontes, Elizabeth P. B.

    2017-01-01

    Plants respond to pathogens using an innate immune system that is broadly divided into PTI (pathogen-associated molecular pattern- or PAMP-triggered immunity) and ETI (effector-triggered immunity). PTI is activated upon perception of PAMPs, conserved motifs derived from pathogens, by surface membrane-anchored pattern recognition receptors (PRRs). To overcome this first line of defense, pathogens release into plant cells effectors that inhibit PTI and activate effector-triggered susceptibility (ETS). Counteracting this virulence strategy, plant cells synthesize intracellular resistance (R) proteins, which specifically recognize pathogen effectors or avirulence (Avr) factors and activate ETI. These coevolving pathogen virulence strategies and plant resistance mechanisms illustrate evolutionary arms race between pathogen and host, which is integrated into the zigzag model of plant innate immunity. Although antiviral immune concepts have been initially excluded from the zigzag model, recent studies have provided several lines of evidence substantiating the notion that plants deploy the innate immune system to fight viruses in a manner similar to that used for non-viral pathogens. First, most R proteins against viruses so far characterized share structural similarity with antibacterial and antifungal R gene products and elicit typical ETI-based immune responses. Second, virus-derived PAMPs may activate PTI-like responses through immune co-receptors of plant PTI. Finally, and even more compelling, a viral Avr factor that triggers ETI in resistant genotypes has recently been shown to act as a suppressor of PTI, integrating plant viruses into the co-evolutionary model of host-pathogen interactions, the zigzag model. In this review, we summarize these important progresses, focusing on the potential significance of antiviral immune receptors and co-receptors in plant antiviral innate immunity. In light of the innate immune system, we also discuss a newly uncovered layer of

  15. Characterization of the effect of Cr(VI) on humoral innate immunity using Drosophila melanogaster.

    PubMed

    Pragya, P; Shukla, A K; Murthy, R C; Abdin, M Z; Kar Chowdhuri, D

    2015-11-01

    With the advancement of human race, different anthropogenic activities have heaped the environment with chemicals that can cause alteration in the immune system of exposed organism. As a first line of barrier, the evolutionary conserved innate immunity is crucial for the health of an organism. However, there is paucity of information regarding in vivo assessment of the effect of environmental chemicals on innate immunity. Therefore, we examined the effect of a widely used environmental chemical, Cr(VI), on humoral innate immune response using Drosophila melanogaster. The adverse effect of Cr(VI) on host humoral response was characterized by decreased gene expression of antimicrobial peptides (AMPs) in the exposed organism. Concurrently, a significantly decreased transcription of humoral pathway receptors (Toll and PGRP) and triglyceride level along with inhibition of antioxidant enzyme activities were observed in exposed organism. This in turn weakened the immune response of exposed organism that was manifested by their reduced resistance against bacterial infection. In addition, overexpression of the components of humoral immunity particularly Diptericin benefits Drosophila from Cr(VI)-induced humoral immune-suppressive effect. To our knowledge, this is the first report regarding negative impact of an environmental chemical on humoral innate immune response of Drosophila along with subsequent protection by AMPs, which may provide novel insight into host-chemical interactions. Also, our data validate the utility and sensitivity of Drosophila as a model that could be used for screening the possible risk of environmental chemicals on innate immunity with minimum ethical concern that can be further extrapolated to higher organisms.

  16. Comparison of Holstein and Jersey innate immune responses to Escherichia coli intramammary infection.

    PubMed

    Bannerman, D D; Kauf, A C W; Paape, M J; Springer, H R; Goff, J P

    2008-06-01

    Mastitis is one of the most prevalent diseases in cattle and remains among the most costly diseases to the dairy industry. Various surveys have indicated a greater prevalence of and risk for mastitis in Holstein cows than in Jersey cows. The innate immune system comprises the immediate host defense mechanisms that respond to infection, and differences in the magnitude and rapidity of this response are known to influence susceptibility to and clearance of infectious pathogens. The reported differences in the prevalence of mastitis between Holstein and Jersey cows may suggest the occurrence of breed-dependent differences in the innate immune response to intramammary infection. The objective of the current study was to compare the acute phase and cytokine responses of Holstein and Jersey cows following intramammary infection by the bacterial pathogen Escherichia coli, a leading cause of clinical mastitis. All cows in the study were in similar stages of lactation, of the same parity, subjected to the same housing and management conditions, and experimentally infected on the same day with the same inoculum preparation. Before and after infection, the following innate immune parameters were monitored: bacterial clearance; febrile response; induction of the acute phase proteins serum amyloid A and lipopolysaccharide-binding protein; alterations in total and differential white blood cell counts; changes in milk somatic cell counts and mammary vascular permeability; and induction of the cytokines IFN-gamma, IL-1beta, IL-8, IL-12, and tumor necrosis factor-alpha. Overall innate immune responses were similar between the 2 breeds; however, temporal differences in the onset, cessation, and duration of several responses were detected. Despite these differences, intramammary clearance of E. coli was comparable between the breeds. Together, these data demonstrate a highly conserved innate immune response of Holstein and Jersey cows to E. coli intramammary infection.

  17. The Impact of Comorbidities on Outcomes for Elderly Women Treated With Breast-Conservation Treatment for Early-Stage Breast Cancer

    SciTech Connect

    Harris, Eleanor E.R. Hwang, W.-T.; Urtishak, Sandra L.; Plastaras, John; Kinosian, Bruce; Solin, Lawrence J.

    2008-04-01

    Purpose: Breast cancer incidence increases with age and is a major cause of morbidity and mortality in elderly women, but is not well studied in this population. Comorbidities often impact on the management of breast cancer in elderly women. Methods and Materials: From 1979 to 2002, a total of 238 women aged 70 years and older with Stage I or II invasive carcinoma of the breast underwent breast-conservation therapy. Outcomes were compared by age groups and comorbidities. Median age at presentation was 74 years (range, 70-89 years). Age distribution was 122 women (51%) aged 70-74 years, 71 women (30%) aged 75-79 years, and 45 women (19%) aged 80 years or older. Median follow-up was 6.2 years. Results: On outcomes analysis by age groups, 10-year cause-specific survival rates for women aged 70-74, 75-79, and 80 years or older were 74%, 81%, and 82%, respectively (p = 0.87). Intercurrent deaths at 10 years were significantly higher in older patients: 20% in those aged 70-74 years, 36% in those aged 75-79 years, and 53% in those 80 years and older (p = 0.0005). Comorbidities were not significantly more common in the older age groups and did not correlate with cause-specific survival adjusted for age. Higher comorbidity scores were associated with intercurrent death. Conclusions: Older age itself is not a contraindication to standard breast-conservation therapy, including irradiation. Women of any age with low to moderate comorbidity indices should be offered standard breast-conservation treatment if otherwise clinically eligible.

  18. Innate immune natural killer cells and their role in HIV and SIV infection

    PubMed Central

    Bostik, Pavel; Takahashi, Yoshiaki; Mayne, Ann E; Ansari, Aftab A

    2010-01-01

    The findings that early events during HIV-1 and SIV infection of Asian rhesus macaques dictate the levels of viremia and rate of disease progression prior to the establishment of mature and effective adaptive immune responses strongly suggest an important role for innate immune mechanisms. In addition, the fact that the major target of HIV and SIV during this period of acute infection is the gastrointestinal tissue suggests that whatever role the innate immune system plays must either directly and/or indirectly focus on the GI tract. The object of this article is to provide a general overview of the innate immune system with a focus on natural killer (NK) cells and their role in the pathogenesis of lentivirus infection. The studies summarized include our current understanding of the phenotypic heterogeneity, the putative functions ascribed to the subsets, the maturation/differentiation of NK cells, the mechanisms by which their function is mediated and regulated, the studies of these NK-cell subsets, with a focus on killer cell immunoglobulin-like receptors (KIRs) in nonhuman primates and humans, and finally, how HIV and SIV infection affects these NK cells in vivo. Clearly much has yet to be learnt on how the innate immune system influences the interaction between lentiviruses and the host within the GI tract, knowledge of which is reasoned to be critical for the formulation of effective vaccines against HIV-1. PMID:20730028

  19. Early endonuclease-mediated evasion of RNA sensing ensures efficient coronavirus replication

    PubMed Central

    Kindler, Eveline; Gil-Cruz, Cristina; Spanier, Julia; Li, Yize; Wilhelm, Jochen; Rabouw, Huib H.; Züst, Roland; Marti, Sabrina; Habjan, Matthias; Cervantes-Barragan, Luisa; Elliot, Ruth; Karl, Nadja; Gaughan, Christina; Silverman, Robert H.; Keller, Markus; Ludewig, Burkhard; Bergmann, Cornelia C.; Ziebuhr, John; Kalinke, Ulrich

    2017-01-01

    Coronaviruses are of veterinary and medical importance and include highly pathogenic zoonotic viruses, such as SARS-CoV and MERS-CoV. They are known to efficiently evade early innate immune responses, manifesting in almost negligible expression of type-I interferons (IFN-I). This evasion strategy suggests an evolutionary conserved viral function that has evolved to prevent RNA-based sensing of infection in vertebrate hosts. Here we show that the coronavirus endonuclease (EndoU) activity is key to prevent early induction of double-stranded RNA (dsRNA) host cell responses. Replication of EndoU-deficient coronaviruses is greatly attenuated in vivo and severely restricted in primary cells even during the early phase of the infection. In macrophages we found immediate induction of IFN-I expression and RNase L-mediated breakdown of ribosomal RNA. Accordingly, EndoU-deficient viruses can retain replication only in cells that are deficient in IFN-I expression or sensing, and in cells lacking both RNase L and PKR. Collectively our results demonstrate that the coronavirus EndoU efficiently prevents simultaneous activation of host cell dsRNA sensors, such as Mda5, OAS and PKR. The localization of the EndoU activity at the site of viral RNA synthesis–within the replicase complex—suggests that coronaviruses have evolved a viral RNA decay pathway to evade early innate and intrinsic antiviral host cell responses. PMID:28158275

  20. Early endonuclease-mediated evasion of RNA sensing ensures efficient coronavirus replication.

    PubMed

    Kindler, Eveline; Gil-Cruz, Cristina; Spanier, Julia; Li, Yize; Wilhelm, Jochen; Rabouw, Huib H; Züst, Roland; Hwang, Mihyun; V'kovski, Philip; Stalder, Hanspeter; Marti, Sabrina; Habjan, Matthias; Cervantes-Barragan, Luisa; Elliot, Ruth; Karl, Nadja; Gaughan, Christina; van Kuppeveld, Frank J M; Silverman, Robert H; Keller, Markus; Ludewig, Burkhard; Bergmann, Cornelia C; Ziebuhr, John; Weiss, Susan R; Kalinke, Ulrich; Thiel, Volker

    2017-02-01

    Coronaviruses are of veterinary and medical importance and include highly pathogenic zoonotic viruses, such as SARS-CoV and MERS-CoV. They are known to efficiently evade early innate immune responses, manifesting in almost negligible expression of type-I interferons (IFN-I). This evasion strategy suggests an evolutionary conserved viral function that has evolved to prevent RNA-based sensing of infection in vertebrate hosts. Here we show that the coronavirus endonuclease (EndoU) activity is key to prevent early induction of double-stranded RNA (dsRNA) host cell responses. Replication of EndoU-deficient coronaviruses is greatly attenuated in vivo and severely restricted in primary cells even during the early phase of the infection. In macrophages we found immediate induction of IFN-I expression and RNase L-mediated breakdown of ribosomal RNA. Accordingly, EndoU-deficient viruses can retain replication only in cells that are deficient in IFN-I expression or sensing, and in cells lacking both RNase L and PKR. Collectively our results demonstrate that the coronavirus EndoU efficiently prevents simultaneous activation of host cell dsRNA sensors, such as Mda5, OAS and PKR. The localization of the EndoU activity at the site of viral RNA synthesis-within the replicase complex-suggests that coronaviruses have evolved a viral RNA decay pathway to evade early innate and intrinsic antiviral host cell responses.

  1. Novel and promiscuous CTL epitopes in conserved regions of Gag targeted by individuals with early subtype C HIV type 1 infection from southern Africa.

    PubMed

    Masemola, Agatha M; Mashishi, Tumelo N; Khoury, Greg; Bredell, Helba; Paximadis, Maria; Mathebula, Tiyani; Barkhan, Debra; Puren, Adrian; Vardas, Efthyia; Colvin, Mark; Zijenah, Lynn; Katzenstein, David; Musonda, Rosemary; Allen, Susan; Kumwenda, Newton; Taha, Taha; Gray, Glenda; McIntyre, James; Karim, Salim Abdool; Sheppard, Haynes W; Gray, Clive M

    2004-10-01

    Characterization of optimal CTL epitopes in Gag can provide crucial information for evaluation of candidate vaccines in populations at the epicenter of the HIV-1 epidemic. We screened 38 individuals with recent subtype C HIV-1 infection using overlapping consensus C Gag peptides and hypothesized that unique HLA-restricting alleles in the southern African population would determine novel epitope identity. Seventy-four percent of individuals recognized at least one Gag peptide pool. Ten epitopic regions were identified across p17, p24, and p2p7p1p6, and greater than two-thirds of targeted regions were directed at: TGTEELRSLYNTVATLY (p17, 35%); GPKEPFRDYVDRFFKTLRAEQATQDV (p24, 19%); and RGGKLDKWEKIRLRPGGKKHYMLKHL (p17, 15%). After alignment of these epitopic regions with consensus M and a consensus subtype C sequence from the cohort, it was evident that the regions targeted were highly conserved. Fine epitope mapping revealed that five of nine identified optimal Gag epitopes were novel: HLVWASREL, LVWASRELERF, LYNTVATLY, PFRDYVDRFF, and TLRAEQATQD, and were restricted by unique HLA-Cw*08, HLA-A*30/B*57, HLA-A*29/B*44, and HLA-Cw*03 alleles, respectively. Notably, three of the mapped epitopes were restricted by more than one HLA allele. Although these epitopes were novel and restricted by unique HLA, they overlapped or were embedded within previously described CTL epitopes from subtype B HIV-1 infection. These data emphasize the promiscuous nature of epitope binding and support our hypothesis that HLA diversity between populations can shape fine epitope identity, but may not represent a constraint for universal recognition of Gag in highly conserved domains.

  2. Long-Term Clinical and Cosmetic Outcomes After Breast Conservation Treatment for Women With Early-Stage Breast Carcinoma According to the Type of Breast Boost

    SciTech Connect

    Hill-Kayser, Christine E.; Chacko, David; Hwang, Wei-Ting; Vapiwala, Neha; Solin, Lawrence J.

    2011-03-15

    Purpose: The present study was performed to compare outcomes after breast conservation treatment with iridium-192 implant boost vs. electron boost. Methods and Materials: From 1977 to 1983, 141 patients were treated with whole breast radiotherapy followed by iridium-192 boost after breast-conserving surgery. They were matched 1:1 to patients treated with electron boost. Outcome measures included survival, local recurrence, cosmesis, and complications. Results: Median follow-up was 16.7 and 12.6 years for the implant vs. electron groups (p < 0.001). Rates of local recurrence, freedom from distant metastases, and overall survival at 10/20 years did not differ between the groups, nor did patterns of first failure. Patients in the electron group were more likely to have excellent/good cosmesis than those in the implant group 1 year after radiotherapy (p = 0.014); this trend continued through 10 years but did not reach statistical significance at years 5/10. Complication rates were similar, although patients receiving electron boost seemed less likely to develop breast fibrosis than did those receiving implant boost (23/141 vs. 58/141, respectively, incidence rate ratio 0.7, p = 0.17). Conclusions: Twenty-year data demonstrate no difference in rates of local recurrence, freedom from distant metastases, overall survival, or patterns of failure between groups treated with these two well-described radiotherapy boost techniques. Better cosmesis was observed in the electron group 1 year after radiotherapy, with a trend continuing for 10 years. The incidence of complications was similar between the groups, with a trend toward increased fibrosis in patients receiving implant boost.

  3. How the Innate Immune System Senses Trouble and Causes Trouble.

    PubMed

    Hato, Takashi; Dagher, Pierre C

    2015-08-07

    The innate immune system is the first line of defense in response to nonself and danger signals from microbial invasion or tissue injury. It is increasingly recognized that each organ uses unique sets of cells and molecules that orchestrate regional innate immunity. The cells that execute the task of innate immunity are many and consist of not only "professional" immune cells but also nonimmune cells, such as renal epithelial cells. Despite a high level of sophistication, deregulated innate immunity is common and contributes to a wide range of renal diseases, such as sepsis-induced kidney injury, GN, and allograft dysfunction. This review discusses how the innate immune system recognizes and responds to nonself and danger signals. In particular, the roles of renal epithelial cells that make them an integral part of the innate immune apparatus of the kidney are highlighted.

  4. [The role of the innate immune system in atopic dermatitis].

    PubMed

    Volz, T; Kaesler, S; Skabytska, Y; Biedermann, T

    2015-02-01

    The mechanisms how the innate immune system detects microbes and mounts a rapid immune response have been more and more elucidated in the past years. Subsequently it has been shown that innate immunity also shapes adaptive immune responses and determines their quality that can be either inflammatory or tolerogenic. As atopic dermatitis is characterized by disturbances of innate and adaptive immune responses, colonization with pathogens and defects in skin barrier function, insight into mechanisms of innate immunity has helped to understand the vicious circle of ongoing skin inflammation seen in atopic dermatitis patients. Elucidating general mechanisms of the innate immune system and its functions in atopic dermatitis paves the way for developing new therapies. Especially the novel insights into the human microbiome and potential functional consequences make the innate immune system a very fundamental and promising target. As a result atopic dermatitis manifestations can be attenuated or even resolved. These currently developed strategies will be introduced in the current review.

  5. Cellular and molecular regulation of innate inflammatory responses

    PubMed Central

    Liu, Juan; Cao, Xuetao

    2016-01-01

    Innate sensing of pathogens by pattern-recognition receptors (PRRs) plays essential roles in the innate discrimination between self and non-self components, leading to the generation of innate immune defense and inflammatory responses. The initiation, activation and resolution of innate inflammatory response are mediated by a complex network of interactions among the numerous cellular and molecular components of immune and non-immune system. While a controlled and beneficial innate inflammatory response is critical for the elimination of pathogens and maintenance of tissue homeostasis, dysregulated or sustained inflammation leads to pathological conditions such as chronic infection, inflammatory autoimmune diseases. In this review, we discuss some of the recent advances in our understanding of the cellular and molecular mechanisms for the establishment and regulation of innate immunity and inflammatory responses. PMID:27818489

  6. Innate immune modulation in EBV infection

    PubMed Central

    2011-01-01

    Epstein-Barr Virus (EBV) belongs to the gammaherpesvirus family, members of which are oncogenic. Compared with other closely related herpesviruses, EBV has developed much more elaborate and sophisticated strategies for subverting host immune system, which may account for its high prevalence in immune competent hosts. Thus, study of EBV-specific immune dysregulation is important for understanding EBV latency and oncogenesis, and will identify potential molecular targets for immunotherapeutic interventions. Here I summarize the recent findings of individual EBV products in regulating host immune responses, with emphasis on the innate immune modulation. PMID:21429244

  7. Transcriptional analysis of the innate immune response using the avian innate immunity microarray

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The avian innate immunity microarray (AIIM) is a genomics tool designed to study the transcriptional activity of the avian immune response (Cytogenet. Genome Res. 117:139-145, 2007). It is an avian cDNA microarray representing 4,959 avian genes spotted in triplicate. The AIIM contains 25 avian int...

  8. [Conservation Units.

    ERIC Educational Resources Information Center

    Texas Education Agency, Austin.

    Each of the six instructional units deals with one aspect of conservation: forests, water, rangeland, minerals (petroleum), and soil. The area of the elementary school curriculum with which each correlates is indicated. Lists of general and specific objectives are followed by suggested teaching procedures, including ideas for introducing the…

  9. [Conservation Units.

    ERIC Educational Resources Information Center

    Texas Education Agency, Austin.

    Instructional units deal with each aspect of conservation: forests, wildlife, rangelands, water, minerals, and soil. The area of the secondary school curriculum with which each is correlated is indicated. Lists of general and specific objectives are followed by suggested teaching procedures, including ideas for introducing the topic, questions to…

  10. Marketing Conservation.

    ERIC Educational Resources Information Center

    Ellis, William B.

    1987-01-01

    In 1986, Northeast Utilities began helping shool administrators combat school building energy wastage through a program called Energy Alliance. The typical school can reduce its energy bill by 30 percent by adopting a wide range of conservation measures, including cogeneration, relamping, and energy audits. (MLH)

  11. Lighting Conservation

    ERIC Educational Resources Information Center

    Arnold, Frank D.

    1975-01-01

    With the energy crisis has come an awareness of wasteful consumption practices. One area where research is being done is in lighting conservation. Information in this article is concerned with finding more effective and efficient lighting designs which include daylight utilization, task-oriented lighting, and lighting controls. (MA)

  12. Colorful Conservation

    ERIC Educational Resources Information Center

    Skophammer, Karen

    2011-01-01

    Some people only think about conservation on Earth Day. Being in the "art business" however, this author is always conscious of the many products she thinks get wasted when they could be reused, recycled, and restored--especially in a school building and art room. In this article, she describes an art lesson that allows students to paint…

  13. OASL – a new player in controlling antiviral innate immunity

    PubMed Central

    Zhu, Jianzhong; Ghosh, Arundhati; Sarkar, Saumendra N.

    2015-01-01

    The cellular innate immune system plays a critical role in mounting the initial resistance to virus infection. It is comprised of various pattern-recognition receptors that induce type I interferon production, which further shapes the adaptive immunity. However, to overcome this resistance and promote replication, viruses have evolved mechanisms to evade this host innate immune response. Here we discuss a recently described mechanism of boosting the innate immunity by oligoadenylate synthetase-like (OASL) protein, which can potentially be used to overcome viral evasion and enhance innate immunity. PMID:25676874

  14. Prophylactic and therapeutic modulation of innate and adaptive immunity against mucosal infection of herpes simplex virus.

    PubMed

    Uyangaa, Erdenebileg; Patil, Ajit Mahadev; Eo, Seong Kug

    2014-08-01

    Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) are the most common cause of genital ulceration in humans worldwide. Typically, HSV-1 and 2 infections via mucosal route result in a lifelong latent infection after peripheral replication in mucosal tissues, thereby providing potential transmission to neighbor hosts in response to reactivation. To break the transmission cycle, immunoprophylactics and therapeutic strategies must be focused on prevention of infection or reduction of infectivity at mucosal sites. Currently, our understanding of the immune responses against mucosal infection of HSV remains intricate and involves a balance between innate signaling pathways and the adaptive immune responses. Numerous studies have demonstrated that HSV mucosal infection induces type I interferons (IFN) via recognition of Toll-like receptors (TLRs) and activates multiple immune cell populations, including NK cells, conventional dendritic cells (DCs), and plasmacytoid DCs. This innate immune response is required not only for the early control of viral replication at mucosal sites, but also for establishing adaptive immune responses against HSV antigens. Although the contribution of humoral immune response is controversial, CD4(+) Th1 T cells producing IFN-γ are believed to play an important role in eradicating virus from the hosts. In addition, the recent experimental successes of immunoprophylactic and therapeutic compounds that enhance resistance and/or reduce viral burden at mucosal sites have accumulated. This review focuses on attempts to modulate innate and adaptive immunity against HSV mucosal infection for the development of prophylactic and therapeutic strategies. Notably, cells involved in innate immune regulations appear to shape adaptive immune responses. Thus, we summarized the current evidence of various immune mediators in response to mucosal HSV infection, focusing on the importance of innate immune responses.

  15. Patterns of pathogenesis: discrimination of pathogenic and non-pathogenic microbes by the innate immune system

    PubMed Central

    Vance, Russell E.; Isberg, Ralph R.; Portnoy, Daniel A.

    2009-01-01

    The dominant conceptual framework for understanding innate immunity has been that host cells respond to evolutionarily conserved molecular features of pathogens called ‘pathogen-associated molecular patterns’ (PAMPs). PAMPs should be understood in the context of how they are naturally presented by pathogens. This can be experimentally challenging since pathogens, almost by definition, bypass host defense. Nevertheless, in this review, we explore the idea that the immune system responds to PAMPs in the context of additional signals that derive from common ‘patterns of pathogenesis’ employed by pathogens to infect, multiply within, and spread among their hosts. PMID:19616762

  16. Innate immunosenescence: effect of aging on cells and receptors of the innate immune system in humans.

    PubMed

    Solana, Rafael; Tarazona, Raquel; Gayoso, Inmaculada; Lesur, Olivier; Dupuis, Gilles; Fulop, Tamas

    2012-10-01

    Components of the innate immune response, including neutrophils and macrophages, are the first line of defense against infections. Their role is to initiate an inflammatory response, phagocyte and kill pathogens, recruit natural killer cells (NK), and facilitate the maturation and migration of dendritic cells that will initiate the adaptive immune response. Extraordinary advances have been made in the last decade on the knowledge of the receptors and mechanisms used by cells of the innate immunity not only to sense and eliminate the pathogen but also to communicate each other and collaborate with cells of adaptive immunity to mount an effective immune response. The analysis of innate immunity in elderly humans has evidenced that aging has a profound impact on the phenotype and functions of these cells. Thus altered expression and/or function of innate immunity receptors and signal transduction leading to defective activation and decreased chemotaxis, phagocytosis and intracellular killing of pathogens have been described. The phenotype and function of NK cells from elderly individuals show significant changes that are compatible with remodeling of the different NK subsets, with a decrease in the CD56bright subpopulation and accumulation of the CD56dim cells, in particular those differentiated NK cells that co-express CD57, as well as a decreased expression of activating natural cytotoxicity receptors. These alterations can be responsible of the decreased production of cytokines and the lower per-cell cytotoxicity observed in the elderly. Considering the relevance of these cells in the initiation of the immune response, the possibility to reactivate the function of innate immune cells should be considered in order to improve the response to pathogens and to vaccination in the elderly.

  17. Fish innate immunity against intestinal helminths.

    PubMed

    Dezfuli, B S; Bosi, G; DePasquale, J A; Manera, M; Giari, L

    2016-03-01

    Most individual fish in farmed and wild populations are infected with parasites. Upon dissection of fish, helminths from gut are often easily visible. Enteric helminths include several species of digeneans, cestodes, acanthocephalans and nematodes. Some insights into biology, morphology and histopathological effects of the main fish enteric helminths taxa will be described here. The immune system of fish, as that of other vertebrates, can be subdivided into specific and aspecific types, which in vivo act in concert with each other and indeed are interdependent in many ways. Beyond the small number of well-described models that exist, research focusing on innate immunity in fish against parasitic infections is lacking. Enteric helminths frequently cause inflammation of the digestive tract, resulting in a series of chemical and morphological changes in the affected tissues and inducing leukocyte migration to the site of infection. This review provides an overview on the aspecific defence mechanisms of fish intestine against helminths. Emphasis will be placed on the immune cellular response involving mast cells, neutrophils, macrophages, rodlet cells and mucous cells against enteric helminths. Given the relative importance of innate immunity in fish, and the magnitude of economic loss in aquaculture as a consequence of disease, this area deserves considerable attention and support.

  18. Domestication changes innate constraints for birdsong learning.

    PubMed

    Kagawa, Hiroko; Suzuki, Kenta; Takahasi, Miki; Okanoya, Kazuo

    2014-07-01

    Birdsongs are acquired by imitating the sounds produced by conspecifics. Within a species, songs diverge by cultural transmission, but the range of species-specific features is restricted by innate constraints. Bengalese finches (Lonchura striata var. domestica) are a domesticated strain of the wild White-rumped munia (Lonchura striata). The songs of the domesticated strain have more tonal sounds and more variable sequences than those of the wild strain. We compared the features of songs that were produced by normal birds, isolation-reared birds, and cross-fostered birds in both White-rumped munias and Bengalese finches to identify differences in the genetic and environmental factors of their songs. Factor analyses were conducted based on 17 song measurements. We found that isolated songs differed from normal and cross-fostered songs, especially in unstable prosodic features. In addition, there were significant differences in sound property of mean frequency between the two strains regardless of the rearing conditions. Thus, innate constraints that partially determine birdsong phenotypes may be altered through domestication.

  19. Immunotherapy for cancer: promoting innate immunity.

    PubMed

    Lotfi, Ramin; Schrezenmeier, Hubert; Lotze, Michael Thomas

    2009-01-01

    Development of tumor over many years leads to reciprocal alterations in the host immune response and the tumor, enabling tumor growth seemingly paradoxically in the setting of necrosis and inflammation. Innate immune cells, granulocytes - neutrophils, eosinophils, basophils - and mast cells belong to the first line of defense sensing pathogen and damage associated molecular pattern (PAMPs, DAMPs) signals, initiating and modulating the subsequent inflammatory response. Nontheless, the prevailing contemporary strategies of immunotherapy for cancer have focused on the second line of the immune response, the adaptive immune response. We have determined that most highly evolved tumors in adults undergo necrosis, releasing DAMPs, promoting reactive angiogenesis, stromagenesis and reparative epithelial proliferation of the tumor cell. Means to aerobically eliminate such DAMPs by peroxidases released by innate immune effectors allows us to consider novel strategies for limiting tumor progression. Summarized here is our current understanding of acute and chronic inflammation and its impact on tumor development, the pathophysiology of immunity in cancer, and the influence of granulocytes and mast cells in this setting.

  20. Innate Immune Responses to AAV Vectors.

    PubMed

    Rogers, Geoffrey L; Martino, Ashley T; Aslanidi, George V; Jayandharan, Giridhara R; Srivastava, Arun; Herzog, Roland W

    2011-01-01

    Gene replacement therapy by in vivo delivery of adeno-associated virus (AAV) is attractive as a potential treatment for a variety of genetic disorders. However, while AAV has been used successfully in many models, other experiments in clinical trials and in animal models have been hampered by undesired responses from the immune system. Recent studies of AAV immunology have focused on the elimination of transgene-expressing cells by the adaptive immune system, yet the innate immune system also has a critical role, both in the initial response to the vector and in prompting a deleterious adaptive immune response. Responses to AAV vectors are primarily mediated by the TLR9-MyD88 pathway, which induces the production of pro-inflammatory cytokines by activating the NF-κB pathways and inducing type I IFN production; self-complementary AAV vectors enhance these inflammatory processes. Additionally, the alternative NF-κB pathway influences transgene expression in cells transduced by AAV. This review highlights these recent discoveries regarding innate immune responses to AAV and discusses strategies to ablate these potentially detrimental signaling pathways.

  1. A Role for PML in Innate Immunity

    PubMed Central

    Lunardi, Andrea; Gaboli, Mirella; Giorgio, Marco; Rivi, Roberta; Bygrave, Anne; Antoniou, Michael; Drabek, Dubravka; Dzierzak, Elaine; Fagioli, Marta; Salmena, Leonardo; Botto, Marina; Cordon-Cardo, Carlos; Luzzatto, Lucio; Pelicci, Pier Giuseppe; Grosveld, Frank; Pandolfi, Pier Paolo

    2011-01-01

    The promyelocytic leukemia gene (PML) of acute promyelocytic leukemia is an established tumor suppressor gene with critical functions in growth suppression, induction of apoptosis, and cellular senescence. Interestingly, although less studied, PML seems to play a key role also in immune response to viral infection. Herein, we report that Pml −/− mice spontaneously develop an atypical invasive and lethal granulomatous lesion known as botryomycosis (BTM). In Pml −/− mice, BTM is the result of impaired function of macrophages, whereby they fail to become activated and are thus unable to clear pathogenic microorganisms. Accordingly, Pml −/− mice are resistant to lipopolysaccharide (LPS)–induced septic shock as a result of an ineffective production of cytokines and chemokines, suggesting a role for PML in the innate immune Toll-like receptor (TLR)/NF-κB prosurvival pathway. These results not only shed light on a new fundamental function of PML in innate immunity, but they also point to a proto-oncogenic role for PML in certain cellular and pathological contexts. PMID:21779477

  2. A comprehensive and conservative approach for the restoration of abrasion and erosion. Part I: concepts and clinical rationale for early intervention using adhesive techniques.

    PubMed

    Dietschi, Didier; Argente, Ana

    2011-01-01

    Tooth wear represents a frequent pathology with multifactorial origins. Behavioral changes, unbalanced diet, various medical conditions and medications inducing acid regurgitation or influencing saliva composition and flow rate, trigger tooth erosion. Awake and sleep bruxism, which are widespread nowadays with functional disorders, induce attrition. It has become increasingly important to diagnose early signs of tooth wear so that proper preventive, and if needed, restorative measures are taken. Such disorders have biological, functional, and also esthetic consequences. Following a comprehensive clinical evaluation, treatment objectives, such as a proper occlusal and anatomical scheme as well as a pleasing smile line, are usually set on models with an anterior teeth full-mouth waxup, depending on the severity of tissue loss. Based on the new vertical dimension of occlusion (VDO), combinations of direct and indirect restorations can then help to reestablish anatomy and function. The use of adhesive techniques and resin composites has demonstrated its potential, in particular for the treatment of moderate tooth wear. Part I of this article reviews recent knowledge and clinical concepts dealing with the various forms of early restorative interventions and their potential to restrict ongoing tissue destruction.

  3. Skin-Sparing Radiation Using Intensity-Modulated Radiotherapy After Conservative Surgery in Early-Stage Breast Cancer: A Planning Study

    SciTech Connect

    Saibishkumar, Elantholi P.; MacKenzie, Marc A.; Severin, Diane; Mihai, Alina; Hanson, John M.Sc.; Daly, Helene; Fallone, Gino; Parliament, Matthew B.; Abdulkarim, Bassam S.

    2008-02-01

    Purpose: To evaluate the feasibility of skin-sparing by configuring it as an organ-at-risk (OAR) while delivering whole-breast intensity-modulated radiotherapy (IMRT) in early breast cancer. Methods and Materials: Archival computed tomography scan images of 14 left-sided early-breast tumor patients who had undergone lumpectomy were selected for this study. Skin was contoured as a 4- to 5-mm strip extending from the patient outline to anterior margin of the breast planning target volume (PTV). Two IMRT plans were generated by the helical tomotherapy approach to deliver 50 Gy in 25 fractions to the breast alone: one with skin dose constraints (skin-sparing plan) and the other without (non-skin-sparing plan). Comparison of the plans was done using a two-sided paired Student t test. Results: The mean skin dose and volume of skin receiving 50 Gy were significantly less with the skin-sparing plan compared with non-skin-sparing plan (42.3 Gy vs. 47.7 Gy and 12.2% vs. 57.8% respectively; p < 0.001). The reduction in skin dose was confirmed by TLD measurements in anthropomorphic phantom using the same plans. Dose-volume analyses for other OARs were similar in both plans. Conclusions: By configuring the skin as an OAR, it is possible to achieve skin dose reduction while delivering whole-breast IMRT without compromising dose profiles to PTV and OARs.

  4. A phase III randomized study on the sequencing of radiotherapy and chemotherapy in the conservative management of early-stage breast cancer

    SciTech Connect

    Arcangeli, Giorgio . E-mail: arcangeli@ifo.it; Pinnaro, Paola; Rambone, Rita; Giannarelli, Diana; Benassi, Marcello

    2006-01-01

    Purpose: To compare two different timings of radiation treatment in patients with breast cancer who underwent conservative surgery and were candidates to receive adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy. Methods and Materials: A total of 206 patients who had quadrantectomy and axillary dissection for breast cancer and were planned to receive adjuvant CMF chemotherapy were randomized to concurrent or sequential radiotherapy. Radiotherapy was delivered only to the whole breast through tangential fields to a dose of 50 Gy in 20 fractions over 4 weeks, followed by an electron boost of 10-15 Gy in 4-6 fractions to the tumor bed. Results: No differences in 5-year breast recurrence-free, metastasis-free, disease-free, and overall survival were observed in the two treatment groups. All patients completed the planned radiotherapy. No evidence of an increased risk of toxicity was observed between the two arms. No difference in radiotherapy and in the chemotherapy dose intensity was observed in the two groups. Conclusions: In patients with negative surgical margins receiving adjuvant chemotherapy, radiotherapy can be delayed to up to 7 months. Concurrent administration of CMF chemotherapy and radiotherapy is safe and might be reserved for patients at high risk of local recurrence, such as those with positive surgical margins or larger tumor diameters.

  5. Cyclic nucleotide gated channels and related signaling components in plant innate immunity.

    PubMed

    Ma, Wei; Smigel, Andries; Verma, Rajeev; Berkowitz, Gerald A

    2009-04-01

    Although plants lack the mobile sentry cells present in animal innate immune systems, plants have developed complex innate immune reactions triggering basal resistance and the hypersensitive response (HR). Cytosolic Ca(2+) elevation is considered to be an important early event in this pathogen response signal transduction cascade. Plasma membrane (PM)-localized cyclic nucleotide gated channels (CNGCs) contribute to the cytosolic Ca(2+) rise upon pathogen perception. Recent work suggests that some PM-localized leucine-rich-repeat receptor-like kinases (LRR-RLKs) may be involved in the perception of pathogen associated molecular pattern molecules and triggering some pathogen responses in plants, some of these LRR-RLKs might have cyclic nucleotide cyclase activity. The recognition of pathogens may be connected to cyclic nucleotide generation and the activation of CNGCs, followed by cytosolic Ca(2+) increase and downstream signaling events (possibly involving nitric oxide, reactive oxygen species (ROS), calmodulin (CaM), CaM-like protein (CML) and protein kinases). Notably, CaM or CML could be the crucial sensor downstream from the early Ca(2+) signal leading to nitric oxide (NO) production during plant innate immune responses.

  6. ACTIN DEPOLYMERIZING FACTOR4 regulates actin dynamics during innate immune signaling in Arabidopsis.

    PubMed

    Henty-Ridilla, Jessica L; Li, Jiejie; Day, Brad; Staiger, Christopher J

    2014-01-01

    Conserved microbe-associated molecular patterns (MAMPs) are sensed by pattern recognition receptors (PRRs) on cells of plants and animals. MAMP perception typically triggers rearrangements to actin cytoskeletal arrays during innate immune signaling. However, the signaling cascades linking PRR activation by MAMPs to cytoskeleton remodeling are not well characterized. Here, we developed a system to dissect, at high spatial and temporal resolution, the regulation of actin dynamics during innate immune signaling in plant cells. Within minutes of MAMP perception, we detected changes to single actin filament turnover in epidermal cells treated with bacterial and fungal MAMPs. These MAMP-induced alterations phenocopied an ACTIN DEPOLYMERIZING FACTOR4 (ADF4) knockout mutant. Moreover, actin arrays in the adf4 mutant were unresponsive to a bacterial MAMP, elf26, but responded normally to the fungal MAMP, chitin. Together, our data provide strong genetic and cytological evidence for the inhibition of ADF activity regulating actin remodeling during innate immune signaling. This work is the first to directly link an ADF/cofilin to the cytoskeletal rearrangements elicited directly after pathogen perception in plant or mammalian cells.

  7. Structural similarities of human and mammalian lipocalins, and their function in innate immunity and allergy.

    PubMed

    Jensen-Jarolim, E; Pacios, L F; Bianchini, R; Hofstetter, G; Roth-Walter, F

    2016-03-01

    Owners and their domestic animals via skin shedding and secretions, mutually exchange microbiomes, potential pathogens and innate immune molecules. Among the latter especially lipocalins are multifaceted: they may have an immunomodulatory function and, furthermore, they represent one of the most important animal allergen families. The amino acid identities, as well as their structures by superposition modeling were compared among human lipocalins, hLCN1 and hLCN2, and most important animal lipocalin allergens, such as Can f 1, Can f 2 and Can f 4 from dog, Fel d 4 from cats, Bos d 5 from cow's milk, Equ c 1 from horses, and Mus m 1 from mice, all of them representing major allergens. The β-barrel fold with a central molecular pocket is similar among human and animal lipocalins. Thereby, lipocalins are able to transport a variety of biological ligands in their highly conserved calyx-like cavity, among them siderophores with the strongest known capability to complex iron (Fe(3+) ). Levels of human lipocalins are elevated in nonallergic inflammation and cancer, associated with innate immunoregulatory functions that critically depend on ligand load. Accordingly, deficient loading of lipocalin allergens establishes their capacity to induce Th2 hypersensitivity. Our similarity analysis of human and mammalian lipocalins highlights their function in innate immunity and allergy.

  8. Oral innate immunity in HIV infection in HAART era

    PubMed Central

    Nittayananta, Wipawee; Tao, Renchuan; Jiang, Lanlan; Peng, Yuanyuan; Huang, Yuxiao

    2015-01-01

    Oral innate immunity, an important component in host defense and immune surveillance in the oral cavity, plays a crucial role in the regulation of oral health. As part of the innate immune system, epithelial cells lining oral mucosal surfaces provide not only a physical barrier but also produce different antimicrobial peptides, including human β-defensins (hBDs), secretory leukocyte protease inhibitor (SLPI), and various cytokines. These innate immune mediators help in maintaining oral homeostasis. When they are impaired either by local or systemic causes, various oral infections and malignancies may be developed. Human immunodeficiency virus (HIV) infection and other co-infections appear to have both direct and indirect effects on systemic and local innate immunity leading to the development of oral opportunistic infections and malignancies. Highly active antiretroviral therapy (HAART), the standard treatment of HIV infection contributed to a global reduction of HIV-associated oral lesions. However, prolonged treatment by HAART may lead to adverse effects on the oral innate immunity resulting in the relapse of oral lesions. This review article focused on the roles of oral innate immunity in HIV infection in HAART era. The following five key questions were addressed: 1) What are the roles of oral innate immunity in health and disease?, 2) What are the effects of HIV infection on oral innate immunity?, 3) What are the roles of oral innate immunity against other co-infections?, 4) What are the effects of HAART on oral innate immunity?, and 5) Is oral innate immunity enhanced by HAART? PMID:25639844

  9. A Prospective Longitudinal Clinical Trial Evaluating Quality of Life After Breast-Conserving Surgery and High-Dose-Rate Interstitial Brachytherapy for Early-Stage Breast Cancer

    SciTech Connect

    Garsa, Adam A.; Ferraro, Daniel J.; DeWees, Todd A.; Deshields, Teresa L.; Margenthaler, Julie A.; Cyr, Amy E.; Naughton, Michael; Aft, Rebecca; Gillanders, William E.; Eberlein, Timothy; Matesa, Melissa A.; Ochoa, Laura L.; Zoberi, Imran

    2013-12-01

    Purpose: To prospectively examine quality of life (QOL) of patients with early stage breast cancer treated with accelerated partial breast irradiation (APBI) using high-dose-rate (HDR) interstitial brachytherapy. Methods and Materials: Between March 2004 and December 2008, 151 patients with early stage breast cancer were enrolled in a phase 2 prospective clinical trial. Eligible patients included those with Tis-T2 tumors measuring ≤3 cm excised with negative surgical margins and with no nodal involvement. Patients received 3.4 Gy twice daily to a total dose of 34 Gy. QOL was measured using European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, version 3.0, and QLQ-BR23 questionnaires. The QLQ-C30 and QLQ-BR23 questionnaires were evaluated during pretreatment and then at 6 to 8 weeks, 3 to 4 months, 6 to 8 months, and 1 and 2 years after treatment. Results: The median follow-up was 55 months. Breast symptom scores remained stable in the months after treatment, and they significantly improved 6 to 8 months after treatment. Scores for emotional functioning, social functioning, and future perspective showed significant improvement 2 years after treatment. Symptomatic fat necrosis was associated with several changes in QOL, including increased pain, breast symptoms, systemic treatment side effects, dyspnea, and fatigue, as well as decreased role functioning, emotional functioning, and social functioning. Conclusions: HDR multicatheter interstitial brachytherapy was well tolerated, with no significant detrimental effect on measured QOL scales/items through 2 years of follow-up. Compared to pretreatment scores, there was improvement in breast symptoms, emotional functioning, social functioning, and future perspective 2 years after treatment.

  10. Cosmetic Analysis Following Breast-Conserving Surgery and Adjuvant High-Dose-Rate Interstitial Brachytherapy for Early-Stage Breast Cancer: A Prospective Clinical Study

    SciTech Connect

    Garsa, Adam A.; Ferraro, Daniel J.; DeWees, Todd; Margenthaler, Julie A.; Naughton, Michael; Aft, Rebecca; Gillanders, William E.; Eberlein, Timothy; Matesa, Melissa A.; Zoberi, Imran

    2013-03-15

    Purpose: To prospectively evaluate cosmetic outcomes in women treated with accelerated partial breast irradiation using high-dose-rate interstitial brachytherapy for early-stage breast cancer. Methods and Materials: Between 2004 and 2008, 151 patients with early-stage breast cancer were enrolled in a phase 2 prospective clinical trial. Eligible patients had stage Tis-T2 tumors of ≤3 cm that were excised with negative margins and with no nodal involvement. Patients received 3.4 Gy twice daily to a total dose of 34 Gy. Both the patients and the treating radiation oncologist qualitatively rated cosmesis as excellent, good, fair, or poor over time and ascribed a cause for changes in cosmesis. Cosmetic outcome was evaluated quantitatively by percentage of breast retraction assessment (pBRA). Patients also reported their satisfaction with treatment over time. Results: Median follow-up was 55 months. The rates of excellent-to-good cosmesis reported by patients and the treating radiation oncologist were 92% and 97% pretreatment, 91% and 97% at 3 to 4 months' follow-up, 87% and 94% at 2 years, and 92% and 94% at 3 years, respectively. Breast infection and adjuvant chemotherapy were independent predictors of a fair-to-poor cosmetic outcome at 3 years. Compared to pretreatment pBRA (7.35), there was no significant change in pBRA over time. The volume receiving more than 150 Gy (V150) was the only significant predictor of pBRA. The majority of patients (86.6%) were completely satisfied with their treatment. Conclusions: Patients and the treating physician reported a high rate of excellent-to-good cosmetic outcomes at all follow-up time points. Acute breast infection and chemotherapy were associated with worse cosmetic outcomes. Multicatheter interstitial brachytherapy does not significantly change breast size as measured by pBRA.

  11. Clinical Factors Associated With Seroma Volume Reduction in Breast-Conserving Therapy for Early-Stage Breast Cancer: A Multi-Institutional Analysis

    SciTech Connect

    Yang, Tzu-I J.; Elkhuizen, Paula H.M.; Minkema, Danny; Heemsbergen, Wilma; Mourik, Anke M. van; Cassee, Jorien; Hurkmans, Coen; Vliet-Vroegindeweij, Corine van

    2010-04-15

    Purpose: To correlate clinical factors with seroma volume and reduction; and to determine whether cone-beam CT (CBCT) could be used clinically to monitor seroma reduction. Patients and Methods: This investigation included 102 women from five institutions with stage T1-2 breast cancer treated with breast-conserving therapy. Two CT scans were acquired: the planning CT (CT1) and a second CT (CT2) during radiotherapy (RT). Seroma was contoured on all scans, and correlations between seroma characteristics and clinical factors were investigated by univariate and multivariate analyses. In a substudy, 10 of the 102 patients received multiple CBCT scans during RT. Seroma were contoured by two observers in the substudy. Fifteen time points at which CT and CBCT were performed within 2 days were identified. The levels of correlation in seroma contours between CBCT and CT and between the two observers were examined. Results: The mean relative seroma reduction from CT1 to CT2 was 54% (p < 0.001). A significant inverse relationship was found between relative seroma reduction per week and number of RT fractions given by univariate and multivariate analyses (p = 0.01, 0.03). The mean difference in contoured seroma volumes between CT and CBCT was 12% (3.3 cm{sup 3}). When assessing the relative difference in seroma contours between Observer 1 and Observer 2, an interobserver difference of 12% was demonstrated. Neither discrepancy was clinically significant. Conclusions: Radiotherapy seems to hinder seroma reduction. Volume discrepancies between CBCT and CT were minor, with low interobserver variation, indicating that CBCT might be useful in monitoring seroma reduction.

  12. Estrogen-Dependent Prognostic Significance of Cyclooxygenase-2 Expression in Early-Stage Invasive Breast Cancers Treated With Breast-Conserving Surgery and Radiation

    SciTech Connect

    Haffty, Bruce G. Yang Qifeng; Moran, Meena S.; Tan, Antoinette R.; Reiss, Michael

    2008-07-15

    Purpose: To evaluate the prognostic significance of cyclooxygenase-2 (COX-2) in breast cancer patients treated with conservative surgery and radiation therapy (CS+RT). Methods and Materials: Between 1975 and 2003, we retrieved specimens from 504 breast cancer patients treated with CS+RT. The specimens were constructed into tissue microarrays processed and stained for estrogen receptor (ER), progesterone receptor, Her2/neu, and COX-2. Each core was scored as positive or negative. All data including demographics, clinical, pathologic, staging, and outcome variables were entered into a computerized database. Results: Expression of COX-2 was positive in 58% of cases and correlated with younger age (p = 0.01) and larger tumor size (p 0.001). Expression of COX-2 was predictive of local relapse (relative risk[RR], 3.248; 95% confidence interval [CI], 1.340-7.871; p = 0.0091), distant metastasis (RR, 2.21; 95% CI, 1.259-3.896; p = 0.0058), and decreased survival (RR, 2.321; 95% CI, 1.324-4.071; p = 0.0033). Among ER-positive patients, COX-2 expression was predictive of worse local control (85% vs. 93%, p = 0.04), distant metastasis (75% vs. 95%, p = 0.002) and worse survival (65% vs. 94%, p = 0.002). Among ER-negative tumors COX-2 expression was not significantly correlated with local control (87 vs. 95%, p = 0.12), distant metastasis (73% vs. 78%, p = 0.39), or survival (77% vs. 87%, p 0.15). Conclusions: In breast cancer patients treated with CS+RT, COX-2 expression is associated with younger age, larger tumor size, worse local control, distant metastasis, and worse overall survival. The significance is limited to hormone receptor-positive tumors, consistent with the known effect of COX-2/PGE2 on aromatase activity. Use of COX-2 inhibitors in estrogen-dependent breast cancers warrants further investigation.

  13. Multiple muscle tear after fall on buttock-role of conservative management and exercise for early recovery and return to play

    PubMed Central

    Adhau, Rajesh; Angrish, Piyush; Ahuja, Ashok; Sandhu, Avtar Singh

    2014-01-01

    Summary Background: to describe role of alternative management as an approach to management and rehabilitation of multiple hip muscles tears by the use of 1 RM (Repetition Maximum) testing and hip muscle strengthening program along with the use of sports specific drills for rehabilitation and recovery. There is very limited literature describing multiple hip muscle tears and the conservative management of the same. 1RM testing and strengthening of hip muscles is an approach that is able to help in the return to sports of an athlete without surgical intervention. Methods: the patient, is a 21-year-old male hockey player who presented with pain right buttock, right lower leg and a limp on the right side while walking. Physical examination revealed a positive Trendelenburg sign both in stance and gait phase. Hip rotational movements showed a normal range of motion, there was a severe pain in the right buttock on movements which he described at 8/10 on VAS (Visual Analogue Scale). Strength assessment revealed weakness of the right hip flexors and extensors and also of the abductor and external hip rotator muscles. Treatment protocol followed was based on 1 RM testing of muscles and hip strengthening exercises and sports specific drills. Results: following the intervention, the patient reported pain at 0/10 VAS while doing all activities and also showed good muscle control with no limp. Conclusions: this highlights an alternative protocol for treating multiple hip muscle tears and illustrates the importance of 1 RM testing as a part of examination and sports medicine intervention. PMID:25332927

  14. Heron conservation

    USGS Publications Warehouse

    Kushlan, J.A.; Hafner, H.

    2000-01-01

    Herons are large, popular and, in many cases, spectacular birds found in wetlands world-wide, both tropical and temperate, natural and man-made. Some populations are very small and localized, some have decreased, some have expanded their ranges, and a few are pests of human activities. In the fifteen years since the publication of the latest monographic treatment of the family, The Herons Handbook, there has been a tremendous increase in our knowledge of heron status and conservation requirements, set against a backdrop of increasing concern about the future of the world?s wetland habitats. This book provides a comprehensive update following two distinct threads. The status and conservation needs of herons are first presented on a regional basis, in a series of chapters set at a continental or subcontinental scale. Over 200 biologists and heron conservationists have contributed to the data summarized here, and the very latest census and survey results provide the most up-to-date and detailed picture of heron populations currently available. Chapters discussing several critical issues in heron conservation follow, tending to focus on the international nature of the problems.

  15. Evolutionary responses of innate Immunity to adaptive immunity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Innate immunity is present in all metazoans, whereas the evolutionarily more novel adaptive immunity is limited to jawed fishes and their descendants (gnathostomes). We observe that the organisms that possess adaptive immunity lack diversity in their innate pattern recognition receptors (PRRs), rais...

  16. Innate immunological function of TH2 cells in vivo

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Th2 cells produce IL-13 when stimulated by papain or house dust mites (HDM) and induce eosinophilic inflammation. This innate response of cells of the adaptive immune system is dependent on IL-33-, not T cell receptor-, based stimulation. While type 2 innate lymphoid cells (ILC2s) are the dominant ...

  17. Pathogen recognition by innate immunity and its signaling

    PubMed Central

    Akira, Shizuo

    2009-01-01

    Mammalian immune response can be divided into innate and acquired immunity. Furthermore, much evidence has demonstrated that activation of innate immunity is a prerequisite to induction of acquired immunity. This paradigm shift has changed our thinking on the pathogenesis and treatment of infections, immune diseases, allergy, and cancers. PMID:19367086

  18. Cell-autonomous stress responses in innate immunity.

    PubMed

    Moretti, Julien; Blander, J Magarian

    2017-01-01

    The innate immune response of phagocytes to microbes has long been known to depend on the core signaling cascades downstream of pattern recognition receptors (PRRs), which lead to expression and production of inflammatory cytokines that counteract infection and induce adaptive immunity. Cell-autonomous responses have recently emerged as important mechanisms of innate immunity. Either IFN-inducible or constitutive, these processes aim to guarantee cell homeostasis but have also been shown to modulate innate immune response to microbes and production of inflammatory cytokines. Among these constitutive cell-autonomous responses, autophagy is prominent and its role in innate immunity has been well characterized. Other stress responses, such as metabolic stress, the ER stress/unfolded protein response, mitochondrial stress, or the DNA damage response, seem to also be involved in innate immunity, although the precise mechanisms by which they regulate the innate immune response are not yet defined. Of importance, these distinct constitutive cell-autonomous responses appear to be interconnected and can also be modulated by microbes and PRRs, which add further complexity to the interplay between innate immune signaling and cell-autonomous responses in the mediation of an efficient innate immune response.

  19. Innatism, Concept Formation, Concept Mastery and Formal Education

    ERIC Educational Resources Information Center

    Winch, Christopher

    2015-01-01

    This article will consider the claim that the possession of concepts is innate rather than learned. Innatism about concept learning is explained through consideration of the work of Fodor and Chomsky. First, an account of concept formation is developed. Second the argument against the claim that concepts are learned through the construction of a…

  20. Innate and acquired bacteriophage-mediated immunity

    PubMed Central

    Barr, Jeremy J.; Youle, Merry; Rohwer, Forest

    2013-01-01

    We recently described a novel, non-host-derived, phage-mediated immunity active at mucosal surfaces, the main site of pathogen entry in metazoans. In that work, we showed that phage T4 adheres to mucus glycoproteins via immunoglobulin-like domains displayed on its capsid. This adherence positions the phage in mucus surfaces where they are more likely to encounter and kill bacteria, thereby benefiting both the phage and its metazoan host. We presented this phage-metazoan symbiosis based on an exclusively lytic model of phage infection. Here we extend our bacteriophage adherence to mucus (BAM) model to consider the undoubtedly more complex dynamics in vivo. We hypothesize how mucus-adherent phages, both lytic and temperate, might impact the commensal microbiota as well as protect the metazoan epithelium from bacterial invasion. We suggest that BAM may provide both an innate and an acquired antimicrobial immunity. PMID:24228227

  1. Ocular Surface as Barrier of Innate Immunity

    PubMed Central

    Bolaños-Jiménez, Rodrigo; Navas, Alejandro; López-Lizárraga, Erika Paulina; de Ribot, Francesc March; Peña, Alexandra; Graue-Hernández, Enrique O; Garfias, Yonathan

    2015-01-01

    Sight is one of the most important senses that human beings possess. The ocular system is a complex structure equipped with mechanisms that prevent or limit damage caused by physical, chemical, infectious and environmental factors. These mechanisms include a series of anatomical, cellular and humoral factors that have been a matter of study. The cornea is not only the most powerful and important lens of the optical system, but also, it has been involved in many other physiological and pathological processes apart from its refractive nature; the morphological and histological properties of the cornea have been thoroughly studied for the last fifty years; drawing attention in its molecular characteristics of immune response. This paper will review the anatomical and physiological aspects of the cornea, conjunctiva and lacrimal apparatus, as well as the innate immunity at the ocular surface. PMID:26161163

  2. Endocannabinoid signalling in innate and adaptive immunity

    PubMed Central

    Chiurchiù, Valerio; Battistini, Luca; Maccarrone, Mauro

    2015-01-01

    The immune system can be modulated and regulated not only by foreign antigens but also by other humoral factors and metabolic products, which are able to affect several quantitative and qualitative aspects of immunity. Among these, endocannabinoids are a group of bioactive lipids that might serve as secondary modulators, which when mobilized coincident with or shortly after first-line immune modulators, increase or decrease many immune functions. Most immune cells express these bioactive lipids, together with their set of receptors and of enzymes regulating their synthesis and degradation. In this review, a synopsis of the manifold immunomodulatory effects of endocannabinoids and their signalling in the different cell populations of innate and adaptive immunity is appointed, with a particular distinction between mice and human immune system compartments. PMID:25585882

  3. Innateness, evolution, and genetics of language.

    PubMed

    Ganger, J; Stromswold, K

    1998-04-01

    Our goal in this article is to review a debate over the evolution of language and to suggest some keys to its resolution. We begin with a review of some of the theoretical and empirical evidence for the innateness of language that has caused renewed interest in the evolution of language. In a second section we review some prominent theories of the evolution of language, focusing on the controversy over whether language could have been adapted for some purpose. We argue that for evolutionary studies of language to advance, theorists must make more persuasive arguments for the purpose of language, and, furthermore, linguists must continue to develop a detailed theory of syntax. Finally, we suggest ways that behavioral and population genetics could help to inform studies of the evolution of language.

  4. Interactions between Innate Immunity, Microbiota, and Probiotics.

    PubMed

    Giorgetti, GianMarco; Brandimarte, Giovanni; Fabiocchi, Federica; Ricci, Salvatore; Flamini, Paolo; Sandri, Giancarlo; Trotta, Maria Cristina; Elisei, Walter; Penna, Antonio; Lecca, Piera Giuseppina; Picchio, Marcello; Tursi, Antonio

    2015-01-01

    The term "microbiota" means genetic inheritance associated with microbiota, which is about 100 times larger than the guest. The tolerance of the resident bacterial flora is an important key element of immune cell function. A key role in the interaction between the host and the microbiota is played by Paneth cell, which is able to synthesize and secrete proteins and antimicrobial peptides, such as α/β defensins, cathelicidin, 14 β-glycosidases, C-type lectins, and ribonuclease, in response to various stimuli. Recent studies found probiotics able to preserve intestinal homeostasis by downmodulating the immune response and inducing the development of T regulatory cells. Specific probiotic strain, as well as probiotic-driven metabolic products called "postbiotics," has been recently recognized and it is able to influence innate immunity. New therapeutic approaches based on probiotics are now available, and further treatments based on postbiotics will come in the future.

  5. Respiratory syncytial virus infection: an innate perspective

    PubMed Central

    Johansson, Cecilia

    2016-01-01

    Respiratory syncytial virus (RSV) is a common cause of upper respiratory tract infection in children and adults. However, infection with this virus sometimes leads to severe lower respiratory disease and is the major cause of infant hospitalisations in the developed world. Several risk factors such as baby prematurity and congenital heart disease are known to predispose towards severe disease but previously healthy, full-term infants can also develop bronchiolitis and viral pneumonia during RSV infection. The causes of severe disease are not fully understood but may include dysregulation of the immune response to the virus, resulting in excessive recruitment and activation of innate and adaptive immune cells that can cause damage. This review highlights recent discoveries on the balancing act of immune-mediated virus clearance versus immunopathology during RSV infection. PMID:28105323

  6. Natural innate and adaptive immunity to cancer.

    PubMed

    Vesely, Matthew D; Kershaw, Michael H; Schreiber, Robert D; Smyth, Mark J

    2011-01-01

    The immune system can identify and destroy nascent tumor cells in a process termed cancer immunosurveillance, which functions as an important defense against cancer. Recently, data obtained from numerous investigations in mouse models of cancer and in humans with cancer offer compelling evidence that particular innate and adaptive immune cell types, effector molecules, and pathways can sometimes collectively function as extrinsic tumor-suppressor mechanisms. However, the immune system can also promote tumor progression. Together, the dual host-protective and tumor-promoting actions of immunity are referred to as cancer immunoediting. In this review, we discuss the current experimental and human clinical data supporting a cancer immunoediting process that provide the fundamental basis for further study of immunity to cancer and for the rational design of immunotherapies against cancer.

  7. Innate immunity in resistance to HIV infection.

    PubMed

    Biasin, Mara; Clerici, Mario; Piacentini, Luca

    2010-11-01

    Resistance to human immunodeficiency virus (HIV) infection in subjects who do not seroconvert despite multiple exposures to the virus and to the progression to AIDS in HIV‐infected individuals depends on multiple factors involving both the innate and the adaptive immune system. The contribution of natural immunity in preventing HIV infection has so far received little attention, but many recently published articles suggest a key role for Toll‐like receptors, natural killer cells, interleukin‐22, acute‐phase amyloid A protein, and APOBEC3G in conferring resistance to HIV infection. The study of these factors will shed light on HIV pathogenesis and contribute to the development of new therapeutic approaches to this elusive disease.

  8. Innate sexuality determines the mechanisms of telomere maintenance.

    PubMed

    Tasaka, Kenta; Yokoyama, Naoki; Nodono, Hanae; Hoshi, Motonori; Matsumoto, Midori

    2013-01-01

    Recently, telomere length has been shown to be differentially regulated in asexually and sexually reproducing planarians. In addition, it was found that asexual worms maintain telomere length somatically during reproduction by fission or when regeneration is induced by amputation, whereas sexual worms only achieve telomere elongation through sexual reproduction. We have established an experimental bioassay system to induce switching from asexual to sexual reproduction in planarians, that is, sexualization. In this study, the relationship between the reproductive mode and telomere maintenance was investigated using innate asexually reproducing worms, innate sexually reproducing worms, and experimentally sexualized worms. Here, we show that innate asexual planarians maintain telomere length during cell division and that innate sexual planarians exhibit telomere shortening. However, experimental sexualized worms maintain telomere length during cell division. These results indicate that innate sexuality is linked to the mechanism of telomere maintenance.

  9. Innate immune response development in nestling tree swallows

    USGS Publications Warehouse

    Stambaugh, T.; Houdek, B.J.; Lombardo, M.P.; Thorpe, P.A.; Caldwell, Hahn D.

    2011-01-01

    We tracked the development of innate immunity in nestling Tree Swallows (Tachycineta bicolor) and compared it to that of adults using blood drawn from nestlings during days 6, 12, and 18 of the ???20-day nestling period and from adults. Innate immunity was characterized using an in vitro assay of the ability of whole blood to kill Escherichia coli. The ability of whole blood to kill E. coli increased as nestlings matured. Neither this component of innate immunity nor right wing chord length on day18 were as developed as in adults indicating that development of the innate immune system and growth both continued after fledging. Narrow sense heritability analyses suggest that females with strong immune responses produced nestlings with strong immune responses. These data suggest nestling Tree Swallows allocated sufficient energy to support rapid growth to enable fledging by day 18, but that further development of innate immunity occurred post-fledging. ?? 2011 by the Wilson Ornithological Society.

  10. Innate Immune Function of TH2 Cells in vivo

    PubMed Central

    Guo, Liying; Huang, Yuefeng; Chen, Xi; Hu-Li, Jane; Urban, Joseph F.; Paul, William E.

    2015-01-01

    Type 2 helper T (TH) cells produce interleukin 13 (IL-13) when stimulated by papain or house dust mites (HDM) and induce eosinophilic inflammation. This innate response is dependent on IL-33 but not T cell antigen receptors (TCRs). While type 2 innate lymphoid cells (ILC2s) are the dominant innate producers of IL-13 in naïve animals, we show here that in helminth-infected mice, TH2 cell numbers increased and became major mediators of innate type II responses. TH2 cells made important contributions to HDM-induced antigen–non-specific eosinophilic inflammation and protected mice recovering from Ascaris suum infection against subsequent infection with the phylogenetically distant nematode Nippostrongylus brasiliensis. Our findings reveal a previously unappreciated role of effector TH2 cells during TCR-independent innate-like immune responses. PMID:26322482

  11. Innate immunological function of TH2 cells in vivo.

    PubMed

    Guo, Liying; Huang, Yuefeng; Chen, Xi; Hu-Li, Jane; Urban, Joseph F; Paul, William E

    2015-10-01

    Type 2 helper T cells (TH2 cells) produce interleukin 13 (IL-13) when stimulated by papain or house dust mite extract (HDM) and induce eosinophilic inflammation. This innate response is dependent on IL-33 but not T cell antigen receptors (TCRs). While type 2 innate lymphoid cells (ILC2 cells) are the dominant innate producers of IL-13 in naive mice, we found here that helminth-infected mice had more TH2 cells compared to uninfected mice, and thes e cells became major mediators of innate type 2 responses. TH2 cells made important contributions to HDM-induced antigen-nonspecific eosinophilic inflammation and protected mice recovering from infection with Ascaris suum against subsequent infection with the phylogenetically distant nematode Nippostrongylus brasiliensis. Our findings reveal a previously unappreciated role for effector TH2 cells during TCR-independent innate-like immune responses.

  12. Innate immunity gene expression changes in critically ill patients with sepsis and disease-related malnutrition

    PubMed Central

    Sarnecka, Agnieszka; Dąbrowska, Aleksandra; Kosałka, Katarzyna; Wachowska, Ewelina; Bałan, Barbara J.; Jankowska, Marta; Korta, Teresa; Niewiński, Grzegorz; Kański, Andrzej; Mikaszewska-Sokolewicz, Małgorzata; Omidi, Mohammad; Majewska, Krystyna; Słotwińska, Sylwia M.

    2015-01-01

    The aim of this study was an attempt to determine whether the expression of genes involved in innate antibacterial response (TL R2, NOD 1, TRAF6, HMGB 1 and Hsp70) in peripheral blood leukocytes in critically ill patients, may undergo significant changes depending on the severity of the infection and the degree of malnutrition. The study was performed in a group of 128 patients with infections treated in the intensive care and surgical ward. In 103/80.5% of patients, infections had a severe course (sepsis, severe sepsis, septic shock, mechanical ventilation of the lungs). Clinical monitoring included diagnosis of severe infection (according to the criteria of the ACC P/SCC M), assessment of severity of the patient condition and risk of death (APACHE II and SAPS II), nutritional assessment (NRS 2002 and SGA scales) and the observation of the early results of treatment. Gene expression at the mRNA level was analyzed by real-time PCR. The results of the present study indicate that in critically ill patients treated in the IC U there are significant disturbances in the expression of genes associated with innate antimicrobial immunity, which may have a significant impact on the clinical outcome. The expression of these genes varies depending on the severity of the patient condition, severity of infection and nutritional status. Expression disorders of genes belonging to innate antimicrobial immunity should be diagnosed as early as possible, monitored during the treatment and taken into account during early therapeutic treatment (including early nutrition to support the functions of immune cells). PMID:26648775

  13. Conserved Organisation of 45S rDNA Sites and rDNA Gene Copy Number among Major Clades of Early Land Plants

    PubMed Central

    Rosato, Marcela; Kovařík, Aleš; Garilleti, Ricardo; Rosselló, Josep A.

    2016-01-01

    Genes encoding ribosomal RNA (rDNA) are universal key constituents of eukaryotic genomes, and the nuclear genome harbours hundreds to several thousand copies of each species. Knowledge about the number of rDNA loci and gene copy number provides information for comparative studies of organismal and molecular evolution at various phylogenetic levels. With the exception of seed plants, the range of 45S rDNA locus (encoding 18S, 5.8S and 26S rRNA) and gene copy number variation within key evolutionary plant groups is largely unknown. This is especially true for the three earliest land plant lineages Marchantiophyta (liverworts), Bryophyta (mosses), and Anthocerotophyta (hornworts). In this work, we report the extent of rDNA variation in early land plants, assessing the number of 45S rDNA loci and gene copy number in 106 species and 25 species, respectively, of mosses, liverworts and hornworts. Unexpectedly, the results show a narrow range of ribosomal locus variation (one or two 45S rDNA loci) and gene copies not present in vascular plant lineages, where a wide spectrum is recorded. Mutation analysis of whole genomic reads showed higher (3-fold) intragenomic heterogeneity of Marchantia polymorpha (Marchantiophyta) rDNA compared to Physcomitrella patens (Bryophyta) and two angiosperms (Arabidopsis thaliana and Nicotiana tomentosifomis) suggesting the presence of rDNA pseudogenes in its genome. No association between phylogenetic position, taxonomic adscription and the number of rDNA loci and gene copy number was found. Our results suggest a likely evolutionary rDNA stasis during land colonisation and diversification across 480 myr of bryophyte evolution. We hypothesise that strong selection forces may be acting against ribosomal gene locus amplification. Despite showing a predominant haploid phase and infrequent meiosis, overall rDNA homogeneity is not severely compromised in bryophytes. PMID:27622766

  14. Conserved Organisation of 45S rDNA Sites and rDNA Gene Copy Number among Major Clades of Early Land Plants.

    PubMed

    Rosato, Marcela; Kovařík, Aleš; Garilleti, Ricardo; Rosselló, Josep A

    2016-01-01

    Genes encoding ribosomal RNA (rDNA) are universal key constituents of eukaryotic genomes, and the nuclear genome harbours hundreds to several thousand copies of each species. Knowledge about the number of rDNA loci and gene copy number provides information for comparative studies of organismal and molecular evolution at various phylogenetic levels. With the exception of seed plants, the range of 45S rDNA locus (encoding 18S, 5.8S and 26S rRNA) and gene copy number variation within key evolutionary plant groups is largely unknown. This is especially true for the three earliest land plant lineages Marchantiophyta (liverworts), Bryophyta (mosses), and Anthocerotophyta (hornworts). In this work, we report the extent of rDNA variation in early land plants, assessing the number of 45S rDNA loci and gene copy number in 106 species and 25 species, respectively, of mosses, liverworts and hornworts. Unexpectedly, the results show a narrow range of ribosomal locus variation (one or two 45S rDNA loci) and gene copies not present in vascular plant lineages, where a wide spectrum is recorded. Mutation analysis of whole genomic reads showed higher (3-fold) intragenomic heterogeneity of Marchantia polymorpha (Marchantiophyta) rDNA compared to Physcomitrella patens (Bryophyta) and two angiosperms (Arabidopsis thaliana and Nicotiana tomentosifomis) suggesting the presence of rDNA pseudogenes in its genome. No association between phylogenetic position, taxonomic adscription and the number of rDNA loci and gene copy number was found. Our results suggest a likely evolutionary rDNA stasis during land colonisation and diversification across 480 myr of bryophyte evolution. We hypothesise that strong selection forces may be acting against ribosomal gene locus amplification. Despite showing a predominant haploid phase and infrequent meiosis, overall rDNA homogeneity is not severely compromised in bryophytes.

  15. The image schema and innate archetypes: theoretical and clinical implications.

    PubMed

    Merchant, John

    2016-02-01

    Based in contemporary neuroscience, Jean Knox's 2004 JAP paper 'From archetypes to reflective function' honed her position on image schemas, thereby introducing a model for archetypes which sees them as 'reliably repeated early developmental achievements' and not as genetically inherited, innate psychic structures. The image schema model is used to illustrate how the analyst worked with a patient who began life as an unwanted pregnancy, was adopted at birth and as an adult experienced profound synchronicities, paranormal/telepathic phenomena and visions. The classical approach to such phenomena would see the intense affectivity arising out of a ruptured symbiotic mother-infant relationship constellating certain archetypes which set up the patient's visions. This view is contrasted with Knox's model which sees the archetype an sich as a developmentally produced image schema underpinning the emergence of later imagery. The patient's visions can then be understood to arise from his psychoid body memory related to his traumatic conception and birth. The contemporary neuroscience which supports this view is outlined and a subsequent image schema explanation is presented. Clinically, the case material suggests that a pre-birth perspective needs to be explored in all analytic work. Other implications of Knox's image schema model are summarized.

  16. Mouse vocal communication system: are ultrasounds learned or innate?

    PubMed Central

    Arriaga, Gustavo; Jarvis, Erich D.

    2013-01-01

    Mouse ultrasonic vocalizations (USVs) are often used as behavioral readouts of internal states, to measure effects of social and pharmacological manipulations, and for behavioral phenotyping of mouse models for neuropsychiatric and neurodegenerative disorders. However, little is known about the neurobiological mechanisms of rodent USV production. Here we discuss the available data to assess whether male mouse song behavior and the supporting brain circuits resemble those of known vocal non-learning or vocal learning species. Recent neurobiology studies have demonstrated that the mouse USV brain system includes motor cortex and striatal regions, and that the vocal motor cortex sends a direct sparse projection to the brainstem vocal motor nucleus ambiguous, a projection thought be unique to humans among mammals. Recent behavioral studies have reported opposing conclusions on mouse vocal plasticity, including vocal ontogeny changes in USVs over early development that might not be explained by innate maturation processes, evidence for and against a role for auditory feedback in developing and maintaining normal mouse USVs, and evidence for and against limited vocal imitation of song pitch. To reconcile these findings, we suggest that the trait of vocal learning may not be dichotomous but encompass a broad set of behavioral and neural traits we call the continuum hypothesis, and that mice possess some of the traits associated with a capacity for limited vocal learning. PMID:23295209

  17. 99th Dahlem Conference on Infection, Inflammation and Chronic Inflammatory Disorders: Innate immune responses in plants

    PubMed Central

    Schulze-Lefert, P

    2010-01-01

    Plants rely exclusively upon mechanisms of innate immunity. Current concepts of the plant innate immune system are based largely on two forms of immunity that engage distinct classes of immune receptors. These receptors enable the recognition of non-self structures that are either conserved between members of a microbial class or specific to individual strains of a microbe. One type of receptor comprises membrane-resident pattern recognition receptors (PRRs) that detect widely conserved microbe-associated molecular patterns (MAMPs) on the cell surface. A second type of mainly intracellular immune sensors, designated resistance (R) proteins, recognizes either the structure or function of strain-specific pathogen effectors that are delivered inside host cells. Phytopathogenic microorganisms have evolved a repertoire of effectors, some of which are delivered into plant cells to sabotage MAMP-triggered immune responses. Plants appear to have also evolved receptors that sense cellular injury by the release and perception of endogenous damage-associated molecular patterns (DAMPs). It is possible that the integration of MAMP and DAMP responses is critical to mount robust MAMP-triggered immunity. This signal integration might help to explain why plants are colonized in nature by remarkably diverse and seemingly asymptomatic microbial communities. PMID:20415853

  18. Drosophila as a Model for Human Diseases-Focus on Innate Immunity in Barrier Epithelia.

    PubMed

    Bergman, P; Seyedoleslami Esfahani, S; Engström, Y

    2017-01-01

    Epithelial immunity protects the host from harmful microbial invaders but also controls the beneficial microbiota on epithelial surfaces. When this delicate balance between pathogen and symbiont is disturbed, clinical disease often occurs, such as in inflammatory bowel disease, cystic fibrosis, or atopic dermatitis, which all can be in part linked to impairment of barrier epithelia. Many innate immune receptors, signaling pathways, and effector molecules are evolutionarily conserved between human and Drosophila. This review describes the current knowledge on Drosophila as a model for human diseases, with a special focus on innate immune-related disorders of the gut, lung, and skin. The discovery of antimicrobial peptides, the crucial role of Toll and Toll-like receptors, and the evolutionary conservation of signaling to the immune systems of both human and Drosophila are described in a historical perspective. Similarities and differences between human and Drosophila are discussed; current knowledge on receptors, signaling pathways, and effectors are reviewed, including antimicrobial peptides, reactive oxygen species, as well as autophagy. We also give examples of human diseases for which Drosophila appears to be a useful model. In addition, the limitations of the Drosophila model are mentioned. Finally, we propose areas for future research, which include using the Drosophila model for drug screening, as a validation tool for novel genetic mutations in humans and for exploratory research of microbiota-host interactions, with relevance for infection, wound healing, and cancer.

  19. Role of the HIN Domain in Regulation of Innate Immune Responses

    PubMed Central

    Shaw, Neil

    2014-01-01

    The oligonucleotide/oligosaccharide binding (OB) fold is employed by proteins to bind nucleic acids during replication, transcription, and translation. Recently, a variation of the OB fold consisting of a tandem pair of OB folds named the HIN (hematopoietic expression, interferon-inducible nature, and nuclear localization) domain was shown to play essential roles in the regulation of innate immune responses originating from binding of nucleic acids in the cytoplasm or the nucleus of the cell. Although the two OB folds of the HIN domain are linked via a long linker region, conserved hydrophobic contacts between the two OB folds hold them together firmly, resulting in a single compact domain. This overall topology of the HIN domain seems to be highly conserved, and proteins containing the HIN domain have been grouped in the PYHIN family. Structures of the recently solved HIN domains reveal that these domains exhibit either absent in melanoma2 (Aim2) HIN-like or p202 HINa-like modes of DNA binding. These two modes of DNA binding seem to result in different responses and as a consequence confer distinct roles on the proteins. This review summarizes our current understanding of the structure and function of the HIN domains in context with the innate immune responses. PMID:24164899

  20. Energy Conservation

    SciTech Connect

    Simpson, P.

    1995-06-01

    There are two fundamental reasons or motivations for energy conservation: (1) economics; and (2) consideration of energy - its sources and availability. Economics speaks for itself and needs little explanation: a project is undertaken, the cost is recovered in a given period of time (we hope) and our company realizes cost savings thereafter. We study and propose a project; we estimate the payback. If approved, we implement the project. Then, we eagerly watch for its effectiveness - for the proposed payback. The second consideration in regard to energy conservation might - in the foreseeable future - become by far the most important - that of availability. Very knowledgeable persons have stated that this - in reality - is the most serious problem facing our nation today. Readily available, reasonably priced energy has given to the US the high form of living experienced today. An interruption in this flow could catapult our nation in an awesome catastrophe. The energy shortage of the late 70`s might be a forerunner of such an experience.

  1. German cockroach frass proteases modulate the innate immune response via activation of protease-activated receptor-2.

    PubMed

    Day, Scottie B; Zhou, Ping; Ledford, John R; Page, Kristen

    2010-01-01

    Allergen exposure can induce an early innate immune response; however, the mechanism by which this occurs has not been addressed. In this report, we demonstrate a role for the active serine proteases in German cockroach (GC) feces (frass) and protease-activated receptor (PAR)-2 in modulating the innate immune response. A single exposure of GC frass induced inflammatory cytokine production and cellular infiltration in the airways of mice. In comparison, exposure to protease-depleted GC frass resulted in diminution of inflammatory cytokine production and airway neutrophilia, but had no effect on macrophage infiltration. Selective activation of PAR-2 confirmed that PAR-2 was sufficient to induce airway inflammation. Exposure of GC frass to PAR-2-deficient mice led to decreased immune responses to GC frass compared to wild-type mice. Using the macrophage as an early marker of the innate immune response, we found that GC frass induced significant release of tumor necrosis factor-alpha from primary alveolar macrophages. This effect was dependent on the intrinsic proteases in GC frass. We confirmed GC frass-induced cytokine expression was mediated by activation of NF-kappaB and ERK in a macrophage cell line. Collectively, these data suggest a central role for GC frass protease-PAR-2 activation in regulating the innate immune response through the activation of alveolar macrophages. Understanding the potential role of protease-PAR-2 activation as a danger signal or adjuvant could yield attractive therapeutic targets.

  2. A critical role for the TLR4/TRIF pathway in allogeneic hematopoietic cell rejection by innate immune cells.

    PubMed

    Xu, Hong; Yan, Jun; Zhu, Ziqiang; Hussain, Lala-Rukh; Huang, Yiming; Ding, Chuanlin; Bozulic, Larry D; Wen, Yujie; Ildstad, Suzanne T

    2013-01-01

    We show for the first time that signaling through the TLR4/TRIF pathway plays a critical role in allogeneic bone marrow cell (BMC) rejection. This appears to be unique to BMCs as organ allografts are rejected mainly via MyD88 signaling. Using T- or T-/B-cell-deficient mice, we found that BMC allorejection occurred early before T-cell activation and was T- and B-cell independent, suggesting an effector role for innate immune cells in BMC rejection. We further demonstrated the innate immune signaling in BMC allorejection by showing superior engraftment in mice deficient in TRIF or TLR4 but not in MyD88 or TLR3. The restored cytotoxicity in TRIF-deficient recipients transferred with wild-type F4/80(+) or NK1.1(+) cells suggests TRIF signaling dependence on macrophages or NK cells in early BMC rejection. Production of the proinflammatory cytokine IL-6 and TRIF relevant chemokine MCP-1 was significantly increased early after bone marrow transplantation. In vivo specific depletion of macrophages or NK innate immune cells in combination with anti-CD154/rapamycin resulted in additive-enhanced allogeneic engraftment. The requirement for irradiation was completely eliminated when both macrophages and NK cells were depleted in combination with anti-CD154/rapamycin to target T- and B-cells, supporting the hypothesis that two barriers involving innate and adaptive immunity exist in mediating the rejection of allogeneic BMCs. In summary, our results clearly demonstrate a previously unappreciated role for innate immunity in BMC allorejection via signaling through a unique MyD88-independent TLR4/TRIF mechanism. These findings may have direct clinical impact on strategies for conditioning recipients for stem cell transplantation.

  3. Mouse nasal epithelial innate immune responses to Pseudomonas aeruginosa quorum-sensing molecules require taste signaling components.

    PubMed

    Lee, Robert J; Chen, Bei; Redding, Kevin M; Margolskee, Robert F; Cohen, Noam A

    2014-08-01

    We previously observed that the human bitter taste receptor T2R38 is an important component of upper respiratory innate defense because it detects acyl homoserine lactone (AHL) quorum-sensing molecules secreted by Gram-negative bacteria. T2R38 activation in human sinonasal epithelial cells stimulates calcium and NO signals that increase mucociliary clearance, the major physical respiratory defense against inhaled pathogens. While mice do not have a clear T2R38 ortholog, they do have bitter taste receptors capable of responding to T2R38 agonists, suggesting that T2R-mediated innate immune mechanisms may be conserved in mice. We examined whether AHLs activate calcium and NO signaling in mouse nasal epithelial cells, and utilized pharmacology, as well as cells from knockout mice lacking important components of canonical taste signal transduction pathways, to determine if AHL-stimulated responses require taste signaling molecules. We found that AHLs stimulate calcium-dependent NO production that increases mucociliary clearance and thus likely serves an innate immune role against Gram-negative bacteria. These responses require PLCβ2 and TRPM5 taste signaling components, but not α-gustducin. These data suggest the mouse may be a useful model for further studies of T2R-mediated innate immunity.

  4. External beam boost versus interstitial high-dose-rate brachytherapy boost in the adjuvant radiotherapy following breast-conserving therapy in early-stage breast cancer: a dosimetric comparison

    PubMed Central

    Melchert, Corinna; Kovács, György

    2016-01-01

    Purpose This study aims to compare the dosimetric data of local tumor's bed dose escalation (boost) with photon beams (external beam radiation therapy – EBRT) versus high-dose-rate interstitial brachytherapy (HDR-BT) after breast-conserving treatment in women with early-stage breast cancer. Material and methods We analyzed the treatment planning data of 136 irradiated patients, treated between 2006 and 2013, who underwent breast-conserving surgery and adjuvant whole breast irradiation (WBI; 50.4 Gy) and boost (HDR-BT: 10 Gy in one fraction [n = 36]; EBRT: 10 Gy in five fractions [n = 100]). Organs at risk (OAR; heart, ipsilateral lung, skin, most exposed rib segment) were delineated. Dosimetric parameters were calculated with the aid of dose-volume histograms (DVH). A non-parametric test was performed to compare the two different boost forms. Results There was no difference for left-sided cancers regarding the maximum dose to the heart (HDR-BT 29.8% vs. EBRT 29.95%, p = 0.34). The maximum doses to the other OAR were significantly lower for HDR-BT (Dmax lung 47.12% vs. 87.7%, p < 0.01; rib 61.17% vs. 98.5%, p < 0.01; skin 57.1% vs. 94.75%, p < 0.01; in the case of right-sided breast irradiation, dose of the heart 6.00% vs. 16.75%, p < 0.01). Conclusions Compared to EBRT, local dose escalation with HDR-BT presented a significant dose reduction to the investigated OAR. Only left-sided irradiation showed no difference regarding the maximum dose to the heart. Reducing irradiation exposure to OAR could result in a reduction of long-term side effects. Therefore, from a dosimetric point of view, an interstitial boost complementary to WBI via EBRT seems to be more advantageous in the adjuvant radiotherapy of breast cancer. PMID:27648082

  5. The innate immune system in human systemic lupus erythematosus.

    PubMed

    Weidenbusch, Marc; Kulkarni, Onkar P; Anders, Hans-Joachim

    2017-04-25

    Although the role of adaptive immune mechanisms, e.g. autoantibody formation and abnormal T-cell activation, has been long noted in the pathogenesis of human systemic lupus erythematosus (SLE), the role of innate immunity has been less well characterized. An intricate interplay between both innate and adaptive immune elements exists in protective anti-infective immunity as well as in detrimental autoimmunity. More recently, it has become clear that the innate immune system in this regard not only starts inflammation cascades in SLE leading to disease flares, but also continues to fuel adaptive immune responses throughout the course of the disease. This is why targeting the innate immune system offers an additional means of treating SLE. First trials assessing the efficacy of anti-type I interferon (IFN) therapy or modulators of pattern recognition receptor (PRR) signalling have been attempted. In this review, we summarize the available evidence on the role of several distinct innate immune elements, especially neutrophils and dendritic cells as well as the IFN system, as well as specific innate PRRs along with their signalling pathways. Finally, we highlight recent clinical trials in SLE addressing one or more of the aforementioned components of the innate immune system.

  6. Enhancing Cancer Immunotherapy Via Activation of Innate Immunity.

    PubMed

    Goldberg, Jacob L; Sondel, Paul M

    2015-08-01

    Given recent technological advances and advances in our understanding of cancer, immunotherapy of cancer is being used with clear clinical benefit. The immunosuppression accompanying cancer itself, as well as with current cancer treatment with radiation or chemotherapy, impairs adaptive immune effectors to a greater extent than innate effector cells. In addition to being less suppressed, innate immune cells are capable of being enhanced via immune-stimulatory regimens. Most strategies being investigated to promote innate immune responses against cancer do not require complex, patient-specific, ex vivo cellular or molecular creation of therapeutic agents; thus they can, generally, be used as "off the shelf" therapeutics that could be administered by most cancer clinics. Successful applications of innate immunotherapy in the clinic have effectively targeted components of the innate immune response. Preclinical data demonstrate how initiation of innate immune responses can lead to subsequent adaptive long-term cancer immunity. We hypothesize that integration of innate immune activation strategies into combination therapies for cancer treatment will lead to more effective and long-term clinical benefit.

  7. Virus-associated activation of innate immunity induces rapid disruption of Peyer's patches in mice.

    PubMed

    Heidegger, Simon; Anz, David; Stephan, Nicolas; Bohn, Bernadette; Herbst, Tina; Fendler, Wolfgang Peter; Suhartha, Nina; Sandholzer, Nadja; Kobold, Sebastian; Hotz, Christian; Eisenächer, Katharina; Radtke-Schuller, Susanne; Endres, Stefan; Bourquin, Carole

    2013-10-10

    Early in the course of infection, detection of pathogen-associated molecular patterns by innate immune receptors can shape the subsequent adaptive immune response. Here we investigate the influence of virus-associated innate immune activation on lymphocyte distribution in secondary lymphoid organs. We show for the first time that virus infection of mice induces rapid disruption of the Peyer's patches but not of other secondary lymphoid organs. The observed effect was not dependent on an active infectious process, but due to innate immune activation and could be mimicked by virus-associated molecular patterns such as the synthetic double-stranded RNA poly(I:C). Profound histomorphologic changes in Peyer's patches were associated with depletion of organ cellularity, most prominent among the B-cell subset. We demonstrate that the disruption is entirely dependent on type I interferon (IFN). At the cellular level, we show that virus-associated immune activation by IFN-α blocks B-cell trafficking to the Peyer's patches by downregulating expression of the homing molecule α4β7-integrin. In summary, our data identify a mechanism that results in type I IFN-dependent rapid but reversible disruption of intestinal lymphoid organs during systemic viral immune activation. We propose that such rerouted lymphocyte trafficking may impact the development of B-cell immunity to systemic viral pathogens.

  8. Essential protective role attributed to the surface lipoproteins of Borrelia burgdorferi against innate defenses

    PubMed Central

    Xu, Qilong; McShan, Kristy; Liang, Fang Ting

    2008-01-01

    Summary To initiate infection, a microbial pathogen must be able to evade innate immunity. Here we show that the Lyme disease spirochete Borrelia burgdorferi depends on its surface lipoproteins for protection against innate defenses. The deficiency for OspC, an abundantly expressed surface lipoprotein during early infection, led to quick clearance of B. burgdorferi after inoculation into the skin of SCID mice. Increasing expression of any of the four randomly chosen surface lipoproteins, OspA, OspE, VlsE or DbpA, fully protected the ospC mutant from elimination from the skin tissue of SCID mice; moreover, increased OspA, OspE, or VlsE expression allowed the mutant to cause disseminated infection and restored the ability to effectively colonize both joint and skin tissues, albeit the dissemination process was much slower than that of the mutant restored with OspC expression. When the ospC mutant was modified to express OspA under control of the ospC regulatory elements, it registered only a slight increase in the 50% infectious dose than the control in SCID mice but a dramatic increase in immunocompetent mice. Taken together, the study demonstrated that the surface lipoproteins provide B. burgdorferi with an essential protective function against host innate elimination. PMID:18452586

  9. Innate immune response of Indian major carp, Labeo rohita infected with oomycete pathogen Aphanomyces invadans.

    PubMed

    Yadav, Manoj K; Pradhan, Pravata K; Sood, Neeraj; Chaudhary, Dharmendra K; Verma, Dev K; Debnath, Chandan; Sahoo, Lopamudra; Chauhan, U K; Punia, Peyush; Jena, Joy K

    2014-08-01

    The fish pathogenic oomycete Aphanomyces invadans is the causative agent of epizootic ulcerative syndrome (EUS), a fish disease of international significance and reportable to the World Organisation for Animal Health. In spite of the current and potential impact of A. invadans infection on fisheries and aquaculture sectors of the world, very little is known about the host-A. invadans interactions. In the present study, following experimental infection with A. invadans in one of the Indian major carps, Labeo rohita, sequential changes in various innate immune parameters were monitored. The results indicated that at early stages of infection, no significant changes in any of the studied innate immune parameters were observed. However, at the advanced stages of infection from 6 to 12 days post infection (dpi), the respiratory burst and alternate complement activity were significantly higher whereas lysozyme, antiproteases and α-2 macroglobulin values were significantly lower than the control group and also from the infected group at earlier stages of infection. Since, the possibility of vaccination of fish against A. invadans appears remote due to difficulties in eliciting a specific antibody response, the information generated in the present study could be useful for developing strategies for improving resistance to A. invadans infection by stimulating the innate immunity through immunomodulation.

  10. Nfil3 is crucial for development of innate lymphoid cells and host protection against intestinal pathogens

    PubMed Central

    Geiger, Theresa L.; Abt, Michael C.; Gasteiger, Georg; Firth, Matthew A.; O’Connor, Margaret H.; Geary, Clair D.; O’Sullivan, Timothy E.; van den Brink, Marcel R.; Pamer, Eric G.; Hanash, Alan M.

    2014-01-01

    The bZIP transcription factor Nfil3 (also known as E4BP4) is required for the development of natural killer (NK) cells and type 1 innate lymphoid cells (ILC1s). We find that Nfil3 plays a critical role in the development of other mucosal tissue-associated innate lymphocytes. Type 3 ILCs (ILC3s), including lymphoid tissue inducer (LTi)–like cells, are severely diminished in both numbers and function in Nfil3-deficient mice. Using mixed bone marrow chimeric mice, we demonstrate that Nfil3 is critical for normal development of gut-associated ILC3s in a cell-intrinsic manner. Furthermore, Nfil3 deficiency severely compromises intestinal innate immune defense against acute bacterial infection with Citrobacter rodentium and Clostridium difficile. Nfil3 deficiency resulted in a loss of the recently identified ILC precursor, yet conditional ablation of Nfil3 in the NKp46+ ILC3 subset did not perturb ILC3 numbers, suggesting that Nfil3 is required early during ILC3 development but not for lineage maintenance. Lastly, a marked defect in type 2 ILCs (ILC2s) was also observed in the lungs and visceral adipose tissue of Nfil3-deficient mice, revealing a general requirement for Nfil3 in the development of all ILC lineages. PMID:25113970

  11. Linking Transcriptional Changes over Time in Stimulated Dendritic Cells to Identify Gene Networks Activated during the Innate Immune Response

    PubMed Central

    Patil, Ashwini; Kumagai, Yutaro; Liang, Kuo-ching; Suzuki, Yutaka; Nakai, Kenta

    2013-01-01

    The innate immune response is primarily mediated by the Toll-like receptors functioning through the MyD88-dependent and TRIF-dependent pathways. Despite being widely studied, it is not yet completely understood and systems-level analyses have been lacking. In this study, we identified a high-probability network of genes activated during the innate immune response using a novel approach to analyze time-course gene expression profiles of activated immune cells in combination with a large gene regulatory and protein-protein interaction network. We classified the immune response into three consecutive time-dependent stages and identified the most probable paths between genes showing a significant change in expression at each stage. The resultant network contained several novel and known regulators of the innate immune response, many of which did not show any observable change in expression at the sampled time points. The response network shows the dominance of genes from specific functional classes during different stages of the immune response. It also suggests a role for the protein phosphatase 2a catalytic subunit α in the regulation of the immunoproteasome during the late phase of the response. In order to clarify the differences between the MyD88-dependent and TRIF-dependent pathways in the innate immune response, time-course gene expression profiles from MyD88-knockout and TRIF-knockout dendritic cells were analyzed. Their response networks suggest the dominance of the MyD88-dependent pathway in the innate immune response, and an association of the circadian regulators and immunoproteasomal degradation with the TRIF-dependent pathway. The response network presented here provides the most probable associations between genes expressed in the early and the late phases of the innate immune response, while taking into account the intermediate regulators. We propose that the method described here can also be used in the identification of time-dependent gene sub

  12. Linking transcriptional changes over time in stimulated dendritic cells to identify gene networks activated during the innate immune response.

    PubMed

    Patil, Ashwini; Kumagai, Yutaro; Liang, Kuo-Ching; Suzuki, Yutaka; Nakai, Kenta

    2013-01-01

    The innate immune response is primarily mediated by the Toll-like receptors functioning through the MyD88-dependent and TRIF-dependent pathways. Despite being widely studied, it is not yet completely understood and systems-level analyses have been lacking. In this study, we identified a high-probability network of genes activated during the innate immune response using a novel approach to analyze time-course gene expression profiles of activated immune cells in combination with a large gene regulatory and protein-protein interaction network. We classified the immune response into three consecutive time-dependent stages and identified the most probable paths between genes showing a significant change in expression at each stage. The resultant network contained several novel and known regulators of the innate immune response, many of which did not show any observable change in expression at the sampled time points. The response network shows the dominance of genes from specific functional classes during different stages of the immune response. It also suggests a role for the protein phosphatase 2a catalytic subunit α in the regulation of the immunoproteasome during the late phase of the response. In order to clarify the differences between the MyD88-dependent and TRIF-dependent pathways in the innate immune response, time-course gene expression profiles from MyD88-knockout and TRIF-knockout dendritic cells were analyzed. Their response networks suggest the dominance of the MyD88-dependent pathway in the innate immune response, and an association of the circadian regulators and immunoproteasomal degradation with the TRIF-dependent pathway. The response network presented here provides the most probable associations between genes expressed in the early and the late phases of the innate immune response, while taking into account the intermediate regulators. We propose that the method described here can also be used in the identification of time-dependent gene sub

  13. Innate immunity in an in vitro murine blastocyst model using embryonic and trophoblast stem cells.

    PubMed

    Aikawa, Hiroaki; Tamai, Miho; Mitamura, Keisuke; Itmainati, Fakhria; Barber, Glen N; Tagawa, Yoh-ichi

    2014-03-01

    The immune system has two broad components-innate and adaptive immunity. Adaptive immunity becomes established only after the onset of hematopoiesis, whereas the innate immune system may be actively protecting organisms from microbial invasion much earlier in development. Here, we address the question of whether the innate immune system functions in the early-stage embryo, i.e., the blastocyst. The innate immune system was studied by using in vitro blastocyst models, e.g., embryonic stem (ES) and trophoblast stem (TS) cell cultures. The expression of Toll-like receptors (TLR)-2, -3, and -5 could be detected in both ES and TS cells. The expression of interferon (IFN)-β was induced by the addition of polyinosinic:polycytidylic acid [poly(I:C)] in TS cells, but not ES cells, although TLR-3 was expressed at the same level in both cell types. In turn, ES cells responded to IFN-β exposure by expressing IFN-induced anti-viral genes, e.g., RNA-dependent protein kinase and 2', 5'-oligoadenylate synthetase (OAS). Neither a reduction in ES cell proliferation nor cell death in these cultures was observed after IFN-β stimulation. Furthermore, OAS1a expression was induced in ES/TS co-cultures after poly(I:C) stimulation, but was not induced when either cell type was cultured alone. In conclusion, TS cells react to poly(I:C) stimulation by producing IFN-β, which induces IFN-inducible genes in ES cells. This observation suggests that the trophectoderm, the outer layer of the blastocyst, may respond to viral infection, and then induce anti-viral gene expression via IFN-β signaling to the blastocyst inner cell mass.

  14. Conservation Education Improvement. Final Report.

    ERIC Educational Resources Information Center

    Diem, Kenneth L.; Hennebry, Howard M.

    In an attempt to improve the teaching of conservation in elementary and junior high schools, a set of integrated sequential core units was formulated and tested in five Wyoming school districts during the fall and early winter of 1968. Based on a total sample of 840 elementary students (38% usable response) and 960 junior high students (49% usable…

  15. Innate antioxidant activity of some traditional formulations

    PubMed Central

    Kaur, Gunpreet; Gupta, Vikas; Bansal, Parveen

    2017-01-01

    Herbal medicine is the oldest form of healthcare known to humanity. Recently, much attention is being directed toward the use of antioxidants. There are some very commonly used Ayurvedic preparations that might have inbuilt antioxidant activity, and their therapeutic potential can be partially attributable to its antioxidant activity. Hence, it was proposed to find out antioxidant activity of such common formulations. Estimation of innate antioxidant activity of some commonly used traditional formulations. In this study, five formulations were evaluated for antioxidant activity in comparison to gallic acid (standard) using the in vitro reducing power method and superoxide radical scavenging activity by dimethyl sulfoxide method followed by calculation of scavenging activity and inhibitory concentration 50% (IC50). The result shows that Ayurvedic drug extracts possess good reducing power and antioxidant activity. Laxmivilas Ras shows higher reducing power ranging from 117 ± 0.021 to 0.176 ± 0.012 as compared to other extracts. The drug extracts were also found to be an efficient scavenger of superoxide radical. The IC50 values for Laxmivilas Ras, Agnitundi Vati, Ajmodadi Churna, Tribhuvankirti Rasa, gallic acid (standard) and Sitopladi Churna, were found to be 50.07, 98.41, 105.13, 116.39, 176.80, and 200.17, respectively. From this study, it can be concluded that the above Ayurvedic formulations possess antioxidant property. However, work could be initiated on the isolation and identification of these antioxidant components. PMID:28217554

  16. Innate olfactory preferences in dung beetles.

    PubMed

    Dormont, Laurent; Jay-Robert, Pierre; Bessière, Jean-Marie; Rapior, Sylvie; Lumaret, Jean-Pierre

    2010-09-15

    The effects of insect larval diet on adult olfactory responses to host-plant or food volatiles are still debated. The induction of adult host preferences has been studied in insects with diverse ecologies, including parasitoids, flower-visitors and phytophagous species. We investigated this question for the first time in a coprophagous insect species. Larvae of the French scarab dung beetle Agrilinus constans were reared on four different artificial substrates containing dung from cattle, horse, sheep or wild boar, and responses of imagos to dung volatiles were then behaviourally tested in an olfactometer. We also reported the first analysis of the composition of different mammal dung volatiles. We showed that adult beetles were more attracted to cattle and sheep dung odours, and that larval feeding experience had no effect on the adult olfactory responses to dung volatiles. A second experiment showed that the presence of other insects inside the dung resource affects the process of dung selection by adults. We identified 64 chemical compounds from dung emissions, and showed that dung volatiles clearly differed among different mammal species, allowing olfactory discrimination by dung beetles. Our results suggest that resource selection in coprophagous insects may be based on innate olfactory preferences. Further experiments should examine whether Agrilinus adults can learn new dung odours, and whether larval diet may influence the behaviour of adults in other coprophagous species.

  17. Innate immunity and inflammation: a transcriptional paradigm.

    PubMed

    Hawiger, J

    2001-01-01

    The innate immune response and the process of inflammation are interwoven. Excessive and continuing cytokine production in response to bacterial lipopolysacharides (LPS) or superantigens is a hallmark of the systemic inflammatory response (IR), which can be life-threatening. Dissemination of these bacterial products induces waves of proinflammatory cytokines that cause vascular injury and multiple organ dysfunction. Both LPS and superantigens induce signaling to the nucleus in mononuclear phagocytes and T cells, respectively. These signaling pathways are mediated by NF-kappaB and other stress-responsive transcription factors (SRTFs), which play a critical role in reprogramming gene expression. The nuclear import of NF-kappaB allows transcriptional activation of over 100 genes that encode mediators of inflammatory and immune responses. We have developed a novel method to block nuclear import of NF-kappaB through cell-permeable peptide transduction in monocytes, macrophages, T lymphocytes, and endothelial cells. Strikingly, a cell-permeable peptide that antagonizes nuclear import of NF-kappaB and other SRTFs, suppressed the systemic production of proinflammatory cytokines (TNFalpha and interferon gamma) in mice challenged with a lethal dose of LPS, and increased their survival by at least 90%. Thus, systemic inflammatory responses are critically dependent on the transcriptional activation ofcytokine genes that are controlled by NF-kappaB and other SRTFs.

  18. Transgenic zebrafish reporter lines reveal conserved Toll-like receptor signaling potential in embryonic myeloid leukocytes and adult immune cell lineages.

    PubMed

    Hall, Chris; Flores, Maria Vega; Chien, Annie; Davidson, Alan; Crosier, Kathryn; Crosier, Phil

    2009-05-01

    The immune response of a host to an invading pathogen is dependent on the capacity of its immune cell compartment to recognize highly conserved pathogen components using an ancient class of pattern recognition receptors known as Toll-like receptors (TLRs). Initiation of TLR-mediated signaling results in the induction of proinflammatory cytokines that help govern the scale and duration of any ensuing response. Specificity for TLR signaling is, in part, a result of the differential recruitment of intracellular adaptor molecules. Of these, MyD88 is required for the majority of TLR signaling. Zebrafish have been shown to possess TLRs and adaptor molecules throughout early development, including MyD88, strongly suggesting conservation of this ancient defense mechanism. However, information about which embryonic cells/tissues possess this conserved signaling potential is lacking. To help define which embryonic cells, in particular, those of the innate immune system, have the potential for MyD88-dependent, TLR-mediated signaling, we generated transgenic reporter lines using regulatory elements of the myd88 gene to drive the fluorescent reporters enhanced GFP and Discosoma red fluorescent protein 2 within live zebrafish. These lines possess fluorescently marked cells/tissues consistent with endogenous myd88 expression, including a subset of myeloid leukocytes. These innate immune cells were confirmed to express other TLR adaptors including Mal, trif, and Sarm. Live wound-healing and infection assays validated the potential of these myd88-expressing leukocytes to participate in immune responses. These lines will provide a valuable resource for further resolving the contribution of MyD88 to early vertebrate immunity.

  19. Afferent lymphatic cannulation as a model system to study innate immune responses to infection and vaccination.

    PubMed

    Neeland, Melanie R; Meeusen, Els N T; de Veer, Michael J

    2014-03-15

    The afferent lymphatics consist of the cells and immunomodulatory signals that are involved in the early response to peripheral stimuli. Examination of this compartment in both homeostatic and stimulatory conditions permits the analysis of the innate biological pathways responsible for the generation of an adaptive immune response in the lymph node. Afferent lymphatic cannulation is therefore an ideal model system to study cellular migration and antigen dispersal kinetics during infection and vaccination. Utilisation of these lymphatic cannulation models has demonstrated the ability to both increase current understanding of infectious diseases, vaccine delivery systems and has the potential to target effector cells and molecules that may be used as novel therapeutic or vaccine targets.

  20. IL-22 is a key player in the regulation of inflammation in fish and involves innate immune cells and PI3K signaling.

    PubMed

    Costa, Maria M; Saraceni, Paolo R; Forn-Cuní, Gabriel; Dios, Sonia; Romero, Alejandro; Figueras, Antonio; Novoa, Beatriz

    2013-12-01

    IL-22 plays a role in various disorders in mammals, including mucosal-associated infections and inflammatory diseases. No functional IL-22 studies have been conducted on non-mammals to date. In this study, recombinant IL-22 (rIL-22) from turbot was produced to investigate its effects as a bioactive molecule. The expression of several pro-inflammatory cytokines was increased after rIL-22 treatment and reduced by pre-treatment with a JAK/STAT inhibitor. The involvement of the PI3K pathway in IL-22 induction was demonstrated. rIL-22 reduced the mortality in Aeromonas salmonicida-infected turbot, while higher Aeromonas hydrophila- or LPS-induced mortality was observed when IL-22 was blocked in zebrafish embryos. IL-22 knockdown increased pro-inflammatory cytokine expression in bacteria-stimulated fish. In zebrafish, IL-22 expression was detected primarily in the myeloid innate linage. It was found during early developmental stages when the adaptive immune response is not yet functional and in rag1(-)/(-) fish that lack an adaptive immune system. Our results clarify the conserved role of IL-22 in lower vertebrates. We suggest for the first time that IL-22 constitutes a key regulator of inflammatory homeostasis even in distant species such as teleosts, which diverged from mammals more than 350 million years ago.

  1. Recombinant oncolytic poliovirus, PVSRIPO, has potent cytotoxic and innate inflammatory effects, mediating therapy in human breast and prostate cancer xenograft models

    PubMed Central

    Holl, Eda K.; Brown, Michael C.; Boczkowski, David; McNamara, Megan A.; George, Daniel J.; Bigner, Darell D.; Gromeier, Matthias; Nair, Smita K.

    2016-01-01

    Intratumoral inoculation of viruses with tumor-selective cytotoxicity may induce cancer cell death and, thereby, shrink neoplastic lesions. It is unlikely, however, that viral tumor cell killing alone could produce meaningful, durable clinical responses, as clinically suitable ‘oncolytic’ viruses are severely attenuated and their spread and propagation are opposed by host immunity. Thus, a more propitious event in this context is the innate antiviral response to intratumoral virus administration, in particular for recruiting durable adaptive immune effector responses. It may represent a double-edged sword, as innate immune activation may eliminate infected tumor cells early, intercept viral spread and block any meaningful therapeutic response. The innate response to viral infection of tumors may be very different from that in non-malignant target tissues, owing to the unusual composition/tissue properties of tumor stroma. In this work, we report investigations of the innate immune response to the oncolytic poliovirus recombinant, PVSRIPO, in two mouse xenotransplantation models for breast and prostate cancer. Our observations indicate short-term virus persistence in infected tumors and virus recovery indicative of modest intratumoral propagation and persistence. Yet, a powerful innate inflammatory response coincided with chemokine induction and myeloid cell infiltration into tumors that was, interestingly, dominated by neutrophils. The combined effect of PVSRIPO tumor infection and the innate response it elicits was significant tumor regression in both models. PMID:27806313

  2. Control of adaptive immunity by the innate immune system

    PubMed Central

    Iwasaki, Akiko; Medzhitov, Ruslan

    2015-01-01

    Microbial infections are recognized by the innate immune system both to elicit immediate defense and to generate long-lasting adaptive immunity. To detect and respond to vastly different groups of pathogens, the innate immune system uses several recognition systems that rely on sensing common structural and functional features associated with different classes of microorganisms. These recognition systems determine microbial location, viability, replication and pathogenicity. Detection of these features by recognition pathways of the innate immune system is translated into different classes of effector responses though specialized populations of dendritic cells. Multiple mechanisms for the induction of immune responses are variations on a common design principle wherein the cells that sense infections produce one set of cytokines to induce lymphocytes to produce another set of cytokines, which in turn activate effector responses. Here we discuss these emerging principles of innate control of adaptive immunity. PMID:25789684

  3. [Bacterial proteases and bacterial resistance against human innate immunity factors].

    PubMed

    Tiurin, Iu A; Mustafin, I G; Fassakhov, R S

    2011-01-01

    The molecular and cell-mediated mechanisms that are developed by certain opportunistic and pathogenic bacteria and were obtained over the course of evolution to preserve resistance against principal components of human body innate immunity are summarized.

  4. Manipulation of Innate and Adaptive Immunity through Cancer Vaccines

    PubMed Central

    Mitchell, Duane A.

    2017-01-01

    Although cancer immunotherapy has shown significant promise in mediating efficacious responses, it remains encumbered by tumor heterogeneity, loss of tumor-specific antigen targets, and the regulatory milieu both regionally and systemically. Cross talk between the innate and adaptive immune response may be requisite to polarize sustained antigen specific immunity. Cancer vaccines can serve as an essential fulcrum in initiating innate immunity while molding and sustaining adaptive immunity. Although peptide vaccines have shown tepid responses in a therapeutic setting with poor correlates for immune activity, RNA vaccines activate innate immune responses and have shown promising effects in preclinical and clinical studies based on enhanced DC migration. While the mechanistic insights behind the interplay between innate and adaptive immunity may be unique to the immunotherapeutic being investigated, understanding this dynamic is important to coordinate the different arms of the immune response in a focused response against cancer antigens. PMID:28265580

  5. The Innate Immune-Related Genes in Catfish

    PubMed Central

    Gao, Lei; He, Chongbo; Liu, Xueguang; Su, Hao; Gao, Xianggang; Li, Yunfeng; Liu, Weidong

    2012-01-01

    Catfish is one of the most important aquaculture species in America (as well as in Asia and Africa). In recent years, the production of catfish has suffered massive financial losses due to pathogen spread and breakouts. Innate immunity plays a crucial role in increasing resistance to pathogenic organisms and has generated increasing interest in the past few years. This review summarizes the current understanding of innate immune-related genes in catfish, including pattern recognition receptors, antimicrobial peptides, complements, lectins, cytokines, transferrin and gene expression profiling using microarrays and next generation sequencing technologies. This review will benefit the understanding of innate immune system in catfish and further efforts in studying the innate immune-related genes in fish. PMID:23203058

  6. Mast cells in allergy: innate instructors of adaptive responses.

    PubMed

    Stelekati, Erietta; Orinska, Zane; Bulfone-Paus, Silvia

    2007-01-01

    The function of mast cells as effector cells in allergy has been extensively studied. However, increasing insight into mast cell physiology has revealed new mast cell functions and has introduced mast cells as key players in the regulation of innate as well as adaptive immunity. For example, mast cells have recently been found to express Toll-like receptors (TLRs), which enable them to participate in the innate immune response against pathogens. Furthermore, mast cells have been reported to interact with B cells, dendritic cells and T cells and thereby modulate the direction of an adaptive immune response. Finally, recent documentation that mast cells express functional MHC class II and costimulatory molecules and release immunologically active exosomes, has raised the possibility that mast cells also engage in (as yet) poorly understood antigen presentation functions. In this review, we explore the hypothesis that mast cells serve as central mediators between innate and adaptive immunity, rather as pure effector cells, during allergic innate responses.

  7. Expression of the Celsr/flamingo homologue, c-fmi1, in the early avian embryo indicates a conserved role in neural tube closure and additional roles in asymmetry and somitogenesis.

    PubMed

    Formstone, Caroline J; Mason, Ivor

    2005-02-01

    Flamingo is one of a core group of proteins that regulate planar cell polarity of epithelial structures within the Drosophila embryo while their vertebrate counterparts have been implicated in the coordination of convergent extension movements during gastrulation and in neural tube closure, suggesting that planar polarity mechanisms also function in these processes. Failure of neural tube closure is one of the most common human birth defects, and a murine flamingo (fmi) homologue, Celsr1/fmi-1, was identified as the defective gene in two mouse mutants exhibiting failure of closure 1 of the neural tube. This failure resulted in craniorachischisis in which the neural tube is open from the midbrain posteriorly. The avian embryo provides a tractable system to study neural tube closure. We have identified a chick Celsr1/fmi-1 orthologue, c-fmi1 and provide the first study of expression of an avian flamingo gene. We show that expression is highly dynamic in the early embryo and that c-fmi1 transcripts become enriched within the avian neural epithelium at the initiation of neural tube closure, suggesting a conserved function for Flamingo proteins in this process. Our data also suggest a role for c-fmi1 in myotome development.

  8. Fungal Surface and Innate Immune Recognition of Filamentous Fungi

    PubMed Central

    Figueiredo, Rodrigo T.; Carneiro, Leticia A. M.; Bozza, Marcelo T.

    2011-01-01

    The innate immune system performs specific detection of molecules from infectious agents through pattern recognition receptors. This recognition triggers inflammatory responses and activation of microbicidal mechanisms by leukocytes. Infections caused by filamentous fungi have increased in incidence and represent an important cause of mortality and morbidity especially in individuals with immunosuppression. This review will discuss the innate immune recognition of filamentous fungi molecules and its importance to infection control and disease. PMID:22194732

  9. Innate immunity's path to the Nobel Prize 2011 and beyond.

    PubMed

    Wagner, Hermann

    2012-05-01

    The 2011 Nobel Prize in Physiology/Medicine to Ralph Steinmann, Jules Hoffmann, and Bruce Beutler recognized a paradigm shift in our understanding of innate immunity, and its impact on adaptive immunity. The Prize highlighted the initial discoveries of Toll's role in immunity in flies, Toll-like receptors in mammals, and the establishment of dendritic cells as the initiators of adaptive immunity. This historical Commentary focuses on the developments in our understanding of innate immunity.

  10. Stress hyperglycemia, insulin treatment, and innate immune cells.

    PubMed

    Xiu, Fangming; Stanojcic, Mile; Diao, Li; Jeschke, Marc G

    2014-01-01

    Hyperglycemia (HG) and insulin resistance are the hallmarks of a profoundly altered metabolism in critical illness resulting from the release of cortisol, catecholamines, and cytokines, as well as glucagon and growth hormone. Recent studies have proposed a fundamental role of the immune system towards the development of insulin resistance in traumatic patients. A comprehensive review of published literatures on the effects of hyperglycemia and insulin on innate immunity in critical illness was conducted. This review explored the interaction between the innate immune system and trauma-induced hypermetabolism, while providing greater insight into unraveling the relationship between innate immune cells and hyperglycemia. Critical illness substantially disturbs glucose metabolism resulting in a state of hyperglycemia. Alterations in glucose and insulin regulation affect the immune function of cellular components comprising the innate immunity system. Innate immune system dysfunction via hyperglycemia is associated with a higher morbidity and mortality in critical illness. Along with others, we hypothesize that reduction in morbidity and mortality observed in patients receiving insulin treatment is partially due to its effect on the attenuation of the immune response. However, there still remains substantial controversy regarding moderate versus intensive insulin treatment. Future studies need to determine the integrated effects of HG and insulin on the regulation of innate immunity in order to provide more effective insulin treatment regimen for these patients.

  11. Estrogen receptors regulate innate immune cells and signaling pathways.

    PubMed

    Kovats, Susan

    2015-04-01

    Humans show strong sex differences in immunity to infection and autoimmunity, suggesting sex hormones modulate immune responses. Indeed, receptors for estrogens (ERs) regulate cells and pathways in the innate and adaptive immune system, as well as immune cell development. ERs are ligand-dependent transcription factors that mediate long-range chromatin interactions and form complexes at gene regulatory elements, thus promoting epigenetic changes and transcription. ERs also participate in membrane-initiated steroid signaling to generate rapid responses. Estradiol and ER activity show profound dose- and context-dependent effects on innate immune signaling pathways and myeloid cell development. While estradiol most often promotes the production of type I interferon, innate pathways leading to pro-inflammatory cytokine production may be enhanced or dampened by ER activity. Regulation of innate immune cells and signaling by ERs may contribute to the reported sex differences in innate immune pathways. Here we review the recent literature and highlight several molecular mechanisms by which ERs regulate the development or functional responses of innate immune cells.

  12. Innate immune targets of hepatitis B virus infection

    PubMed Central

    Zou, Zhi-Qiang; Wang, Li; Wang, Kai; Yu, Ji-Guang

    2016-01-01

    Approximately 400 million people are chronically infected with hepatitis B virus (HBV) globally despite the widespread immunization of HBV vaccine and the development of antiviral therapies. The immunopathogenesis of HBV infection is initiated and driven by complexed interactions between the host immune system and the virus. Host immune responses to viral particles and proteins are regarded as the main determinants of viral clearance or persistent infection and hepatocyte injury. Innate immune system is the first defending line of host preventing from virus invasion. It is acknowledged that HBV has developed active tactics to escape innate immune recognition or actively interfere with innate immune signaling pathways and induce immunosuppression, which favor their replication. HBV reduces the expression of pattern-recognition receptors in the innate immune cells in humans. Also, HBV may interrupt different parts of antiviral signaling pathways, leading to the reduced production of antiviral cytokines such as interferons that contribute to HBV immunopathogenesis. A full comprehension of the mechanisms as to how HBV inactivates various elements of the innate immune response to initiate and maintain a persistent infection can be helpful in designing new immunotherapeutic methods for preventing and eradicating the virus. In this review, we aimed to summarize different branches the innate immune targeted by HBV infection. The review paper provides evidence that multiple components of immune responses should be activated in combination with antiviral therapy to disrupt the tolerance to HBV for eliminating HBV infection. PMID:27330680

  13. Innate immune targets of hepatitis B virus infection.

    PubMed

    Zou, Zhi-Qiang; Wang, Li; Wang, Kai; Yu, Ji-Guang

    2016-06-18

    Approximately 400 million people are chronically infected with hepatitis B virus (HBV) globally despite the widespread immunization of HBV vaccine and the development of antiviral therapies. The immunopathogenesis of HBV infection is initiated and driven by complexed interactions between the host immune system and the virus. Host immune responses to viral particles and proteins are regarded as the main determinants of viral clearance or persistent infection and hepatocyte injury. Innate immune system is the first defending line of host preventing from virus invasion. It is acknowledged that HBV has developed active tactics to escape innate immune recognition or actively interfere with innate immune signaling pathways and induce immunosuppression, which favor their replication. HBV reduces the expression of pattern-recognition receptors in the innate immune cells in humans. Also, HBV may interrupt different parts of antiviral signaling pathways, leading to the reduced production of antiviral cytokines such as interferons that contribute to HBV immunopathogenesis. A full comprehension of the mechanisms as to how HBV inactivates various elements of the innate immune response to initiate and maintain a persistent infection can be helpful in designing new immunotherapeutic methods for preventing and eradicating the virus. In this review, we aimed to summarize different branches the innate immune targeted by HBV infection. The review paper provides evidence that multiple components of immune responses should be activated in combination with antiviral therapy to disrupt the tolerance to HBV for eliminating HBV infection.

  14. Hepatocytes: a key cell type for innate immunity

    PubMed Central

    Zhou, Zhou; Xu, Ming-Jiang; Gao, Bin

    2016-01-01

    Hepatocytes, the major parenchymal cells in the liver, play pivotal roles in metabolism, detoxification, and protein synthesis. Hepatocytes also activate innate immunity against invading microorganisms by secreting innate immunity proteins. These proteins include bactericidal proteins that directly kill bacteria, opsonins that assist in the phagocytosis of foreign bacteria, iron-sequestering proteins that block iron uptake by bacteria, several soluble factors that regulate lipopolysaccharide signaling, and the coagulation factor fibrinogen that activates innate immunity. In this review, we summarize the wide variety of innate immunity proteins produced by hepatocytes and discuss liver-enriched transcription factors (e.g. hepatocyte nuclear factors and CCAAT/enhancer-binding proteins), pro-inflammatory mediators (e.g. interleukin (IL)-6, IL-22, IL-1β and tumor necrosis factor-α), and downstream signaling pathways (e.g. signal transducer and activator of transcription factor 3 and nuclear factor-κB) that regulate the expression of these innate immunity proteins. We also briefly discuss the dysregulation of these innate immunity proteins in chronic liver disease, which may contribute to an increased susceptibility to bacterial infection in patients with cirrhosis. PMID:26685902

  15. Innate immune reconstitution with suppression of HIV-1

    PubMed Central

    Scully, Eileen P.; Garcia-Beltran, Wilfredo; Palmer, Christine D.; Musante, Chelsey; Rosenberg, Eric; Allen, Todd M.; Bosch, Ronald J.

    2016-01-01

    Progressive HIV-1 infection leads to both profound immune suppression and pathologic inflammation in the majority of infected individuals. While adaptive immune dysfunction, as evidenced by CD4+ T cell depletion and exhaustion, has been extensively studied, less is known about the functional capacity of innate immune cell populations in the context of HIV-1 infection. Given the broad susceptibility to opportunistic infections and the dysregulated inflammation observed in progressive disease, we hypothesized that there would be significant changes in the innate cellular responses. Using a cohort of patients with multiple samplings before and after antiretroviral therapy (ART) initiation, we demonstrated increased responses to innate immune stimuli following viral suppression, as measured by the production of inflammatory cytokines. Plasma viral load itself had the strongest association with this change in innate functional capacity. We further identified epigenetic modifications in the TNFA promoter locus in monocytes that are associated with viremia, suggesting a molecular mechanism for the observed changes in innate immune function following initiation of ART. These data indicate that suppression of HIV-1 viremia is associated with changes in innate cellular function that may in part determine the restoration of protective immune responses. PMID:27158667

  16. Diminished Innate Antiviral Response to Adenovirus Vectors in cGAS/STING-Deficient Mice Minimally Impacts Adaptive Immunity

    PubMed Central

    Anghelina, Daniela; Lam, Eric

    2016-01-01

    ABSTRACT Infection by adenovirus, a nonenveloped DNA virus, induces antiviral innate and adaptive immune responses. Studies of transformed human and murine cell lines using short hairpin RNA (shRNA) knockdown strategies identified cyclic guanine adenine synthase (cGAS) as a pattern recognition receptor (PRR) that contributes to the antiadenovirus response. Here we demonstrate how the cGAS/STING cascade influences the antiviral innate and adaptive immune responses in a murine knockout model. Using knockout bone marrow-derived dendritic cells (BMDCs) and bone marrow-derived macrophages (BMMOs), we determined that cGAS and STING are essential to the induction of the antiadenovirus response in these antigen-presenting cells (APCs) in vitro. We next determined how the cGAS/STING cascade impacts the antiviral response following systemic administration of a recombinant adenovirus type 5 vector (rAd5V). Infection of cGAS−/− and STING−/− mice results in a compromised early antiviral innate response compared to that in wild-type (WT) controls: significantly lower levels of beta interferon (IFN-β) secretion, low levels of proinflammatory chemokine induction, and reduced levels of antiviral transcript induction in hepatic tissue. At 24 h postinfection, levels of viral DNA and reporter gene expression in the liver were similar in all strains. At 28 days postinfection, clearance of infected hepatocytes in cGAS or STING knockout mice was comparable to that in WT C57BL/6 mice. Levels of neutralizing anti-Ad5V antibody were modestly reduced in infected cGAS mice. These data support a dominant role for the cGAS/STING cascade in the early innate antiviral inflammatory response to adenovirus vectors. However, loss of the cGAS/STING pathway did not affect viral clearance, and cGAS deficiency had a modest influence on the magnitude of the antiviral humoral immune response to adenovirus infections. IMPORTANCE The detection of viral infection by host sentinel immune cells

  17. Acquired and innate immunity to polyaromatic hydrocarbons

    SciTech Connect

    Yusuf, Nabiha Timares, Laura; Seibert, Megan D.; Xu Hui; Elmets, Craig A.

    2007-11-01

    Polyaromatic hydrocarbons are ubiquitous environmental pollutants that are potent mutagens and carcinogens. Researchers have taken advantage of these properties to investigate the mechanisms by which chemicals cause cancer of the skin and other organs. When applied to the skin of mice, several carcinogenic polyaromatic hydrocarbons have also been shown to interact with the immune system, stimulating immune responses and resulting in the development of antigen-specific T-cell-mediated immunity. Development of cell-mediated immunity is strain-specific and is governed by Ah receptor genes and by genes located within the major histocompatibility complex. CD8{sup +} T cells are effector cells in the response, whereas CD4{sup +} T cells down-regulate immunity. Development of an immune response appears to have a protective effect since strains of mice that develop a cell-mediated immune response to carcinogenic polyaromatic hydrocarbons are less likely to develop tumors when subjected to a polyaromatic hydrocarbon skin carcinogenesis protocol than mice that fail to develop an immune response. With respect to innate immunity, TLR4-deficient C3H/HeJ mice are more susceptible to polyaromatic hydrogen skin tumorigenesis than C3H/HeN mice in which TLR4 is normal. These findings support the hypothesis that immune responses, through their interactions with chemical carcinogens, play an active role in the prevention of chemical skin carcinogenesis during the earliest stages. Efforts to augment immune responses to the chemicals that cause tumors may be a productive approach to the prevention of tumors caused by these agents.

  18. Effect of the Ketone Body Beta-Hydroxybutyrate on the Innate Defense Capability of Primary Bovine Mammary Epithelial Cells

    PubMed Central

    Flinspach, Claudia; Pfaffl, Michael W.; Kliem, Heike

    2016-01-01

    Negative energy balance and ketosis are thought to cause impaired immune function and to increase the risk of clinical mastitis in dairy cows. The present in vitro study aimed to investigate the effect of elevated levels of the predominant ketone body β-hydroxybutyrate on the innate defense capability of primary bovine mammary epithelial cells (pbMEC) challenged with the mastitis pathogen Escherichia coli (E. coli). Therefore, pbMEC of healthy dairy cows in mid- lactation were isolated from milk and challenged in culture with 3 mM BHBA and E. coli. pbMEC stimulated with E. coli for 6 h or 30 h showed an up-regulation of several innate immune genes, whereas co-stimulation of pbMEC with 3 mM BHBA and E. coli resulted in the down-regulation of CCL2, SAA3, LF and C3 gene expression compared to the challenge with solely the bacterial stimulus. These results indicated that increased BHBA concentrations may be partially responsible for the higher mastitis susceptibility of dairy cows in early lactation. Elevated levels of BHBA in blood and milk during negative energy balance and ketosis are likely to impair innate immune function in the bovine mammary gland by attenuating the expression of a broad range of innate immune genes. PMID:27310007

  19. Evolution and Conservation of Plant NLR Functions

    PubMed Central

    Jacob, Florence; Vernaldi, Saskia; Maekawa, Takaki

    2013-01-01

    In plants and animals, nucleotide-binding domain and leucine-rich repeats (NLR)-containing proteins play pivotal roles in innate immunity. Despite their similar biological functions and protein architecture, comparative genome-wide analyses of NLRs and genes encoding NLR-like proteins suggest that plant and animal NLRs have independently arisen in evolution. Furthermore, the demonstration of interfamily transfer of plant NLR functions from their original species to phylogenetically distant species implies evolutionary conservation of the underlying immune principle across plant taxonomy. In this review we discuss plant NLR evolution and summarize recent insights into plant NLR-signaling mechanisms, which might constitute evolutionarily conserved NLR-mediated immune mechanisms. PMID:24093022

  20. Defective innate immunity and hyperinflammation in newborn cystic fibrosis transmembrane conductance regulator-knockout ferret lungs.

    PubMed

    Keiser, Nicholas W; Birket, Susan E; Evans, Idil A; Tyler, Scott R; Crooke, Adrianne K; Sun, Xingshen; Zhou, Weihong; Nellis, Joseph R; Stroebele, Elizabeth K; Chu, Kengyeh K; Tearney, Guillermo J; Stevens, Mark J; Harris, J Kirk; Rowe, Steven M; Engelhardt, John F

    2015-06-01

    Mucociliary clearance (MCC) and submucosal glands are major components of airway innate immunity that have impaired function in cystic fibrosis (CF). Although both of these defense systems develop postnatally in the ferret, the lungs of newborn ferrets remain sterile in the presence of a functioning cystic fibrosis transmembrane conductance regulator gene. We evaluated several components of airway innate immunity and inflammation in the early CF ferret lung. At birth, the rates of MCC did not differ between CF and non-CF animals, but the height of the airway surface liquid was significantly reduced in CF newborn ferrets. CF ferrets had impaired MCC after 7 days of age, despite normal rates of ciliogenesis. Only non-CF ferrets eradicated Pseudomonas directly introduced into the lung after birth, whereas both genotypes could eradicate Staphylococcus. CF bronchoalveolar lavage fluid (BALF) had significantly lower antimicrobial activity selectively against Pseudomonas than non-CF BALF, which was insensitive to changes in pH and bicarbonate. Liquid chromatography-tandem mass spectrometry and cytokine analysis of BALF from sterile Caesarean-sectioned and nonsterile naturally born animals demonstrated CF-associated disturbances in IL-8, TNF-α, and IL-β, and pathways that control immunity and inflammation, including the complement system, macrophage functions, mammalian target of rapamycin signaling, and eukaryotic initiation factor 2 signaling. Interestingly, during the birth transition, IL-8 was selectively induced in CF BALF, despite no genotypic difference in bacterial load shortly after birth. These results suggest that newborn CF ferrets have defects in both innate immunity and inflammatory signaling that may be important in the early onset and progression of lung disease in these animals.

  1. HIV-1 evades innate immune recognition through specific cofactor recruitment

    NASA Astrophysics Data System (ADS)

    Rasaiyaah, Jane; Tan, Choon Ping; Fletcher, Adam J.; Price, Amanda J.; Blondeau, Caroline; Hilditch, Laura; Jacques, David A.; Selwood, David L.; James, Leo C.; Noursadeghi, Mahdad; Towers, Greg J.

    2013-11-01

    Human immunodeficiency virus (HIV)-1 is able to replicate in primary human macrophages without stimulating innate immunity despite reverse transcription of genomic RNA into double-stranded DNA, an activity that might be expected to trigger innate pattern recognition receptors. We reasoned that if correctly orchestrated HIV-1 uncoating and nuclear entry is important for evasion of innate sensors then manipulation of specific interactions between HIV-1 capsid and host factors that putatively regulate these processes should trigger pattern recognition receptors and stimulate type 1 interferon (IFN) secretion. Here we show that HIV-1 capsid mutants N74D and P90A, which are impaired for interaction with cofactors cleavage and polyadenylation specificity factor subunit 6 (CPSF6) and cyclophilins (Nup358 and CypA), respectively, cannot replicate in primary human monocyte-derived macrophages because they trigger innate sensors leading to nuclear translocation of NF-κB and IRF3, the production of soluble type 1 IFN and induction of an antiviral state. Depletion of CPSF6 with short hairpin RNA expression allows wild-type virus to trigger innate sensors and IFN production. In each case, suppressed replication is rescued by IFN-receptor blockade, demonstrating a role for IFN in restriction. IFN production is dependent on viral reverse transcription but not integration, indicating that a viral reverse transcription product comprises the HIV-1 pathogen-associated molecular pattern. Finally, we show that we can pharmacologically induce wild-type HIV-1 infection to stimulate IFN secretion and an antiviral state using a non-immunosuppressive cyclosporine analogue. We conclude that HIV-1 has evolved to use CPSF6 and cyclophilins to cloak its replication, allowing evasion of innate immune sensors and induction of a cell-autonomous innate immune response in primary human macrophages.

  2. NK Cells Alleviate Lung Inflammation by Negatively Regulating Group 2 Innate Lymphoid Cells.

    PubMed

    Bi, Jiacheng; Cui, Lulu; Yu, Guang; Yang, Xiaolu; Chen, Youhai; Wan, Xiaochun

    2017-03-08

    Group 2 innate lymphoid cells (ILC2s) play an important role in orchestrating type II immune responses. However, the cellular mechanisms of group 2 innate lymphoid cell regulation remain poorly understood. In this study, we found that activated NK cells inhibited the proliferation of, as well as IL-5 and IL-13 production by, ILC2s in vitro via IFN-γ. In addition, in a murine model of ILC2 expansion in the liver, polyinosinic-polycytidylic acid, an NK cell-activating agent, inhibited ILC2 proliferation, IL-5 and IL-13 production, and eosinophil recruitment. Such effects of polyinosinic-polycytidylic acid were abrogated in NK cell-depleted mice and in IFN-γ-deficient mice. Adoptively transferring wild-type NK cells into NK cell-depleted mice resulted in fewer ILC2s induced by IL-33 compared with the transfer of IFN-γ-deficient NK cells. Importantly, during the early stage of papain- or bleomycin-induced lung inflammation, depletion of NK cells resulted in increased ILC2 numbers and enhanced cytokine production by ILC2s, as well as aggravated eosinophilia and goblet cell hyperplasia. Collectively, these data show that NK cells negatively regulate ILC2s during the early stage of lung inflammation, which represents the novel cellular interaction between two family members of ILCs.

  3. Neutrophil extracellular trap formation as innate immune reactions against the apicomplexan parasite Eimeria bovis.

    PubMed

    Behrendt, Jan Hillern; Ruiz, Antonio; Zahner, Horst; Taubert, Anja; Hermosilla, Carlos

    2010-01-15

    Eimeria bovis infections are under immunological control and recent studies have emphasized the role of early PMN-mediated innate immune responses in infected calves. Neutrophil extracellular traps (NETs) have recently been demonstrated to act as a killing mechanism of PMN against several pathogens. In the present study, the interactions of bovine PMN with sporozoites of E. bovis were investigated in this respect in vitro. For demonstration and quantification of NET formation, extracellular DNA was stained by Sytox Orange. Fluorescence images after Sytox Orange staining as well as scanning electron microscopy (SEM) showed NET formation to occur upon contact with E. bovis sporozoites. Exposure of PMN to viable sporozoites induced stronger NET formation than to dead or homogenized parasites. NET formation was abolished by treatment with DNase and could be reduced by diphenylene iodonium, which is described as a potent inhibitor of NADPH oxidase. After sporozoite and PMN co-culture, extracellular fibres were found attached to sporozoites and seemed to trap them, strongly suggesting that NETs immobilize E. bovis sporozoites and thereby prevent them from infecting host cells. Thus, transfer of sporozoites, previously being confronted with PMN, to adequate host cells resulted in clearly reduced infection rates when compared to PMN-free controls. NET formation by PMN may therefore represent an effector mechanism in early innate immune reactions against E. bovis. This is the first report indicating Eimeria-induced NET formation.

  4. Pathogen-accelerated atherosclerosis occurs early after exposure and can be prevented via immunization.

    PubMed

    Miyamoto, Takanari; Yumoto, Hiromichi; Takahashi, Yusuke; Davey, Michael; Gibson, Frank C; Genco, Caroline Attardo

    2006-02-01

    Here we report on early inflammatory events associated with Porphyromonas gingivalis-accelerated atherosclerosis in apolipoprotein E knockout (ApoE-/-) mice. Animals challenged with P. gingivalis presented with increased macrophage infiltration, innate immune marker expression, and atheroma without elevated systemic inflammatory mediators. This early local inflammatory response was prevented in mice immunized with P. gingivalis. We conclude that localized up-regulation of innate immune markers early after infection, rather than systemic inflammation, contributes to pathogen-accelerated atherosclerosis.

  5. γδ T cells come to stay: Innate skin memory in the Aldara model.

    PubMed

    Prinz, Immo; Sandrock, Inga

    2015-11-01

    The term immunological memory has long been a trademark restricted to adaptive lymphocytes such as memory B cells and plasma cells as well as memory CD8(+) αβ T cells. In recent years, innate lymphocytes such as NK cells have also been shown to adapt to their environment by antigen-specific expansion and selective survival. However, whether γδ T cells mount comparable memory responses to pathogenic stimuli is less well understood. In this issue of European Journal of Immunology, Hartwig et al. [Eur. J. Immunol. 2015. 45: 3022-3033] identify a subset of IL-17-producing γδ T cells that are capable of establishing long-lived memory in the skin of mice exposed to imiquimod in the Aldara psoriasis model. These γδ T cells uniformly express a Vγ4(+) Vδ4(+) TCR. They produce IL-17A/F and persist in the dermis for long periods of time, also at untreated distal sites. Upon secondary challenge, experienced Vγ4(+) Vδ4(+) cells show enhanced effector functions and mediate exacerbated secondary inflammation. These findings showcase innate γδ T-cell memory that uses a single conserved public TCR combination. Furthermore, they provide mechanistic insight to the observed psoriatic relapses in patients in response to topical treatment with imiquimod.

  6. NLR proteins: integral members of innate immunity and mediators of inflammatory diseases

    PubMed Central

    Wilmanski, Jeanette M.; Petnicki-Ocwieja, Tanja; Kobayashi, Koichi S.

    2012-01-01

    The innate immune system is the first line of defense against microorganisms and is conserved in both plants and animals. The NLR protein family is a recent addition to the members of innate immunity effector molecules. These proteins are characterized by a central oligomerization domain termed NACHT (or NBD/NOD) and a protein interaction domain, LRRs (Leucine rich repeats) at the C-terminus. It has been shown that NLR proteins are localized to the cytoplasm and recognize microbial products. To date, it is known that Nod1 and Nod2 detect bacterial cell wall components, whereas IPAF and NAIP detect bacterial flagellin and NALP1 has been shown to detect anthrax lethal toxin. NLR proteins comprise a diverse protein family (over 20 in humans), indicating that NLRs have evolved to acquire specificity to various pathogenic microorganisms, thereby controlling host-pathogen interactions. Activation of NLR proteins results in inflammatory responses mediated either by NF-κB, MAPK or Caspase-1 activation, accompanied by subsequent secretion of pro-inflammatory cytokines. Mutations in several members of the NLR protein family have been linked to inflammatory diseases, suggesting these molecules play important roles in maintaining host-pathogen interaction and inflammatory responses. Therefore, understanding NLR signaling is important for the therapeutic intervention of various infectious and inflammatory diseases. PMID:17875812

  7. Structural basis for concerted recruitment and activation of IRF-3 by innate immune adaptor proteins

    PubMed Central

    Zhao, Baoyu; Shu, Chang; Gao, Xinsheng; Sankaran, Banumathi; Du, Fenglei; Shelton, Catherine L.; Herr, Andrew B.; Ji, Jun-Yuan; Li, Pingwei

    2016-01-01

    Type I IFNs are key cytokines mediating innate antiviral immunity. cGMP-AMP synthase, ritinoic acid-inducible protein 1 (RIG-I)–like receptors, and Toll-like receptors recognize microbial double-stranded (ds)DNA, dsRNA, and LPS to induce the expression of type I IFNs. These signaling pathways converge at the recruitment and activation of the transcription factor IRF-3 (IFN regulatory factor 3). The adaptor proteins STING (stimulator of IFN genes), MAVS (mitochondrial antiviral signaling), and TRIF (TIR domain-containing adaptor inducing IFN-β) mediate the recruitment of IRF-3 through a conserved pLxIS motif. Here we show that the pLxIS motif of phosphorylated STING, MAVS, and TRIF binds to IRF-3 in a similar manner, whereas residues upstream of the motif confer specificity. The structure of the IRF-3 phosphomimetic mutant S386/396E bound to the cAMP response element binding protein (CREB)-binding protein reveals that the pLxIS motif also mediates IRF-3 dimerization and activation. Moreover, rotavirus NSP1 (nonstructural protein 1) employs a pLxIS motif to target IRF-3 for degradation, but phosphorylation of NSP1 is not required for its activity. These results suggest a concerted mechanism for the recruitment and activation of IRF-3 that can be subverted by viral proteins to evade innate immune responses. PMID:27302953

  8. The STING controlled cytosolic-DNA activated innate immune pathway and microbial disease.

    PubMed

    Konno, Hiroyasu; Barber, Glen N

    2014-12-01

    The innate immune system is critically important for the primary sensing of invading pathogens. Over the past decade, the cellular sensors important for recognizing microbial entry into the host cell have been largely elucidated. These sensors, some of which are evolutionarily conserved, include the Toll-like receptor (TLR) and RIG-I-like helicase family (RLH) pathway that can recognize bacterial and viral non-self nucleic acid. In addition, a cellular sensor referred to as STING (for stimulator of interferon genes) has been shown to be critical for triggering host defense countermeasures, including stimulation of the adaptive immune response, following the detection of cytosolic DNA species. The STING pathway has now been shown to be critical for activating innate immune gene transcription in response to infection by DNA pathogens such as herpes simplex virus 1 (HSV1) as well as retroviruses. In addition, it is clear that chronic STING activation can also cause autoinflammatory disease manifested by self-DNA. Here we review recent developments in our understanding of STING function, including importance in the control of microbial disease.

  9. Interim Cosmetic Results and Toxicity Using 3D Conformal External Beam Radiotherapy to Deliver Accelerated Partial Breast Irradiation in Patients With Early-Stage Breast Cancer Treated With Breast-Conserving Therapy

    SciTech Connect

    Vicini, Frank A. Chen, Peter; Wallace, Michelle; Mitchell, Christina; Hasan, Yasmin; Grills, Inga; Kestin, Larry; Schell, Scott; Goldstein, Neal S.; Kunzman, Jonathan; Gilbert, Sam; Martinez, Alvaro

    2007-11-15

    Purpose: We present our ongoing clinical experience utilizing three-dimensional (3D)-conformal radiation therapy (3D-CRT) to deliver accelerated partial breast irradiation (APBI) in patients with early-stage breast cancer treated with breast-conserving therapy. Methods and Materials: Ninety-one consecutive patients were treated with APBI using our previously reported 3D-CRT technique. The clinical target volume consisted of the lumpectomy cavity plus a 10- to 15 -mm margin. The prescribed dose was 34 or 38.5 Gy in 10 fractions given over 5 consecutive days. The median follow-up was 24 months. Twelve patients have been followed for {>=}4 years, 20 for {>=}3.5 years, 29 for >3.0 years, 33 for {>=}2.5 years, and 46 for {>=}2.0 years. Results: No local recurrences developed. Cosmetic results were rated as good/excellent in 100% of evaluable patients at {>=} 6 months (n = 47), 93% at 1 year (n = 43), 91% at 2 years (n = 21), and in 90% at {>=}3 years (n = 10). Erythema, hyperpigmentation, breast edema, breast pain, telangiectasias, fibrosis, and fat necrosis were evaluated at 6, 24, and 36 months after treatment. All factors stabilized by 3 years posttreatment with grade I or II rates of 0%, 0%, 0%, 0%, 9%, 18%, and 9%, respectively. Only 2 patients (3%) developed grade III toxicity (breast pain), which resolved with time. Conclusions: Delivery of APBI with 3D-CRT resulted in minimal chronic ({>=}6 months) toxicity to date with good/excellent cosmetic results. Additional follow-up is needed to assess the long-term efficacy of this form of APBI.

  10. Identification and isolation of stimulator of interferon genes (STING): an innate immune sensory and adaptor gene from camelids.

    PubMed

    Premraj, A; Aleyas, A G; Nautiyal, B; Rasool, T J

    2013-10-01

    The mechanism by which type I interferon-mediated antiviral response is mounted by hosts against invading pathogen is an intriguing one. Of late, an endoplasmic reticulum transmembrane protein encoded by a gene called stimulator of interferon genes (STING) is implicated in the innate signalling pathways and has been identified and cloned in few mammalian species including human, mouse and pig. In this article, we report the identification of STING from three different species of a highly conserved family of mammals - the camelids. cDNAs encoding the STING of Old World camels - dromedary camel (Camelus dromedarius) and bactrian camel (Camelus bactrianus) and a New World camel - llama (Llama glama) were amplified using conserved primers and RACE. The complete STING cDNA of dromedary camel is 2171 bp long with a 706-bp 5' untranslated regions (UTR), an 1137-bp open reading frame (ORF) and a 328-bp 3' UTR. Sequence and phylogenetic analysis of the ORF of STING from these three camelids indicate high level of similarity among camelids and conservation of critical amino acid residues across different species. Quantitative real-time PCR analysis revealed high levels of STING mRNA expression in blood, spleen, lymph node and lung. The identification of camelid STING will help in better understanding of the role of this molecule in the innate immunity of the camelids and other mammals.

  11. Sunitinib treatment enhances metastasis of innately drug resistant breast tumors

    PubMed Central

    Wragg, Joseph W; Heath, Victoria L; Bicknell, Roy

    2017-01-01

    Anti-angiogenic therapies have failed to confer survival benefits in patients with metastatic breast cancer (mBC). However, to date there has not been an inquiry into roles for acquired versus innate drug resistance in this setting. In this study, we report roles for these distinct phenotypes in determining therapeutic response in a murine model of mBC resistance to the anti-angiogenic tyrosine kinase inhibitor sunitinib. Using tumor measurement and vascular patterning approaches, we differentiated tumors displaying innate versus acquired resistance. Bioluminescent imaging of tumor metastases to the liver, lungs and spleen revealed that sunitinib administration enhances metastasis, but only in tumors displaying innate resistance to therapy. Transcriptomic analysis of tumors displaying acquired versus innate resistance allowed the identification of specific biomarkers, many of which have a role in angiogenesis. In particular, aquaporin-1 upregulation occurred in acquired resistance, mTOR in innate resistance, and pleiotrophin in both settings, suggesting their utility as candidate diagnostics to predict drug response or to design tactics to circumvent resistance. Our results unravel specific features of antiangiogenic resistance, with potential therapeutic implications. PMID:28011623

  12. Local Innate Responses to TLR Ligands in the Chicken Trachea

    PubMed Central

    Barjesteh, Neda; Alkie, Tamiru Negash; Hodgins, Douglas C.; Nagy, Éva; Sharif, Shayan

    2016-01-01

    The chicken upper respiratory tract is the portal of entry for respiratory pathogens, such as avian influenza virus (AIV). The presence of microorganisms is sensed by pathogen recognition receptors (such as Toll-like receptors (TLRs)) of the innate immune defenses. Innate responses are essential for subsequent induction of potent adaptive immune responses, but little information is available about innate antiviral responses of the chicken trachea. We hypothesized that TLR ligands induce innate antiviral responses in the chicken trachea. Tracheal organ cultures (TOC) were used to investigate localized innate responses to TLR ligands. Expression of candidate genes, which play a role in antiviral responses, was quantified. To confirm the antiviral responses of stimulated TOC, chicken macrophages were treated with supernatants from stimulated TOC, prior to infection with AIV. The results demonstrated that TLR ligands induced the expression of pro-inflammatory cytokines, type I interferons and interferon stimulated genes in the chicken trachea. In conclusion, TLR ligands induce functional antiviral responses in the chicken trachea, which may act against some pathogens, such as AIV. PMID:27455308

  13. Viral degradasome hijacks mitochondria to suppress innate immunity

    PubMed Central

    Goswami, Ramansu; Majumdar, Tanmay; Dhar, Jayeeta; Chattopadhyay, Saurabh; Bandyopadhyay, Sudip K; Verbovetskaya, Valentina; Sen, Ganes C; Barik, Sailen

    2013-01-01

    The balance between the innate immunity of the host and the ability of a pathogen to evade it strongly influences pathogenesis and virulence. The two nonstructural (NS) proteins, NS1 and NS2, of respiratory syncytial virus (RSV) are critically required for RSV virulence. Together, they strongly suppress the type I interferon (IFN)-mediated innate immunity of the host cells by degrading or inhibiting multiple cellular factors required for either IFN induction or response pathways, including RIG-I, IRF3, IRF7, TBK1 and STAT2. Here, we provide evidence for the existence of a large and heterogeneous degradative complex assembled by the NS proteins, which we named “NS-degradasome” (NSD). The NSD is roughly ∼300-750 kD in size, and its degradative activity was enhanced by the addition of purified mitochondria in vitro. Inside the cell, the majority of the NS proteins and the substrates of the NSD translocated to the mitochondria upon RSV infection. Genetic and pharmacological evidence shows that optimal suppression of innate immunity requires mitochondrial MAVS and mitochondrial motility. Together, we propose a novel paradigm in which the mitochondria, known to be important for the innate immune activation of the host, are also important for viral suppression of the innate immunity. PMID:23877405

  14. Alemtuzumab treatment alters circulating innate immune cells in multiple sclerosis

    PubMed Central

    Ahmetspahic, Diana; Ruck, Tobias; Schulte-Mecklenbeck, Andreas; Schwarte, Kathrin; Jörgens, Silke; Scheu, Stefanie; Windhagen, Susanne; Graefe, Bettina; Melzer, Nico; Klotz, Luisa; Arolt, Volker; Wiendl, Heinz; Meuth, Sven G.

    2016-01-01

    Objective: To characterize changes in myeloid and lymphoid innate immune cells in patients with relapsing-remitting multiple sclerosis (MS) during a 6-month follow-up after alemtuzumab treatment. Methods: Circulating innate immune cells including myeloid cells and innate lymphoid cells (ILCs) were analyzed before and 6 and 12 months after onset of alemtuzumab treatment. Furthermore, a potential effect on granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)–23 production by myeloid cells and natural killer (NK) cell cytolytic activity was determined. Results: In comparison to CD4+ T lymphocytes, myeloid and lymphoid innate cell subsets of patients with MS expressed significantly lower amounts of CD52 on their cell surface. Six months after CD52 depletion, numbers of circulating plasmacytoid dendritic cells (DCs) and conventional DCs were reduced compared to baseline. GM-CSF and IL-23 production in DCs remained unchanged. Within the ILC compartment, the subset of CD56bright NK cells specifically expanded under alemtuzumab treatment, but their cytolytic activity did not change. Conclusions: Our findings demonstrate that 6 months after alemtuzumab treatment, specific DC subsets are reduced, while CD56bright NK cells expanded in patients with MS. Thus, alemtuzumab specifically restricts the DC compartment and expands the CD56bright NK cell subset with potential immunoregulatory properties in MS. We suggest that remodeling of the innate immune compartment may promote long-term efficacy of alemtuzumab and preserve immunocompetence in patients with MS. PMID:27766281

  15. The Critical Role of Innate Immunity in Kidney Transplantation.

    PubMed

    Cucchiari, David; Podestà, Manuel Alfredo; Ponticelli, Claudio

    2016-01-01

    For a long time now, kidney transplant rejection has been considered the consequence of either cellular or antibody-mediated reaction as a part of adaptive immunity response. The role of innate immunity, on the other hand, had been unclear for many years and was thought to be only ancillary. There is now consistent evidence that innate immune response is a condition necessary to activate the machinery of rejection. In this setting, the communication between antigen-presenting cells and T lymphocytes is of major importance. Indeed, T cells are unable to cause rejection if innate immunity is not activated. This field is currently being explored and several experiments in animal models have proved that blocking innate immunity activation can promote tolerance of the graft instead of rejection. The aim of this review is to systematically describe all the steps of innate immunity response in kidney transplant rejection, from antigen recognition to T-cells activation, with a focus on clinical consequences and possible future perspectives.

  16. Trained immunity: A smart way to enhance innate immune defence.

    PubMed

    van der Meer, Jos W M; Joosten, Leo A B; Riksen, Niels; Netea, Mihai G

    2015-11-01

    The innate arm of the immune system is generally viewed as primitive and non-specific and - in contrast to the adaptive immune arm - not to possess memory. However in plants and invertebrate animals that lack adaptive immunity, innate immunity will exhibit a prolonged enhanced functional state after adequate priming. A similar enhancement of function of the innate immunity has occasionally been described in vertebrates, including humans. Over the past few years we have studied this phenomenon in greater detail and we have coined the term 'Trained (innate) immunity' (TI). TI can be induced by a variety of stimuli, of which we have studied BCG and β-glucan in greater detail. The non-specific protective effects of BCG that have been observed in vaccination studies in the literature are probably due to TI. Monocytes and macrophages are among the main cells of the innate immune arm that can be trained. We have discovered that both BCG (via NOD2 signalling) and β-glucan (via dectin-1) induce epigenetic reprogramming, in particular stable changes in histone trimethylation at H3K4. These epigenetic changes lead to cellular activation, enhanced cytokine production and a change in the metabolic state of the cell with a shift from oxidative phosphorylation to aerobic glycolysis. TI is not only important for host defence and vaccine responses, but most probably also for diseases like atherosclerosis. Modulation of TI is a promising area for new treatments.

  17. A cross-disciplinary perspective on the innate immune responses to bacterial lipopolysaccharide

    PubMed Central

    Tan, Yunhao; Kagan, Jonathan C

    2014-01-01

    The study of innate immunity to bacteria has focused heavily on the mechanisms by which mammalian cells detect lipopolysaccharide (LPS), the conserved surface component of gram-negative bacteria. While Toll-like Receptor 4 (TLR4) is responsible for all the host transcriptional responses to LPS, recent discoveries have revealed the existence of several TLR4-independent responses to LPS. These discoveries not only broaden our view of the means by which mammalian cells interact with bacteria, but also highlight new selective pressures that may have promoted the evolution of bacterial immune evasion strategies. In this review, we highlight past and recent discoveries on host LPS sensing mechanisms and discuss bacterial countermeasures that promote infection. By looking at both sides of the host-pathogen interaction equation, we hope to provide comprehensive insights into host defense mechanisms and bacterial pathogenesis. PMID:24766885

  18. Arginase 1 is an innate lymphoid-cell-intrinsic metabolic checkpoint controlling type 2 inflammation.

    PubMed

    Monticelli, Laurel A; Buck, Michael D; Flamar, Anne-Laure; Saenz, Steven A; Tait Wojno, Elia D; Yudanin, Naomi A; Osborne, Lisa C; Hepworth, Matthew R; Tran, Sara V; Rodewald, Hans-Reimer; Shah, Hardik; Cross, Justin R; Diamond, Joshua M; Cantu, Edward; Christie, Jason D; Pearce, Erika L; Artis, David

    2016-06-01

    Group 2 innate lymphoid cells (ILC2s) regulate tissue inflammation and repair after activation by cell-extrinsic factors such as host-derived cytokines. However, the cell-intrinsic metabolic pathways that control ILC2 function are undefined. Here we demonstrate that expression of the enzyme arginase-1 (Arg1) during acute or chronic lung inflammation is a conserved trait of mouse and human ILC2s. Deletion of mouse ILC-intrinsic Arg1 abrogated type 2 lung inflammation by restraining ILC2 proliferation and dampening cytokine production. Mechanistically, inhibition of Arg1 enzymatic activity disrupted multiple components of ILC2 metabolic programming by altering arginine catabolism, impairing polyamine biosynthesis and reducing aerobic glycolysis. These data identify Arg1 as a key regulator of ILC2 bioenergetics that controls proliferative capacity and proinflammatory functions promoting type 2 inflammation.

  19. Arginase 1 is an innate lymphoid cell-intrinsic metabolic checkpoint controlling type 2 inflammation

    PubMed Central

    Monticelli, Laurel A; Buck, Michael D; Flamar, Anne-Laure; Saenz, Steven A; Wojno, Elia D Tait; Yudanin, Naomi A; Osborne, Lisa C; Hepworth, Matthew R; Tran, Sara V; Rodewald, Hans-Reimer; Shah, Hardik; Cross, Justin R; Diamond, Joshua M; Cantu, Edward; Christie, Jason D; Pearce, Erika L; Artis, David

    2016-01-01

    Group 2 innate lymphoid cells (ILC2s) regulate tissue inflammation and repair following activation by cell-extrinsic factors including host-derived cytokines. However, the cell-intrinsic metabolic pathways that control ILC2 function are undefined. Here we demonstrate that expression of the enzyme Arginase 1 (Arg1) is a conserved trait of murine and human ILC2s during acute or chronic lung inflammation. Deletion of murine ILC-intrinsic Arg1 abrogated type 2 lung inflammation by restraining ILC2 proliferation and dampening cytokine production. Mechanistically, inhibition of Arg1 enzymatic activity disrupted multiple components of ILC2 metabolic programming by altering arginine catabolism, impairing polyamine biosynthesis and reducing aerobic glycolysis. These data identify Arg1 as a key regulator of ILC2 bioenergetics, controlling proliferative capacity and pro-inflammatory functions that promote type 2 inflammation. PMID:27043409

  20. Akirin specifies NF-κB selectivity of Drosophila innate immune response via chromatin remodeling

    PubMed Central

    Bonnay, François; Nguyen, Xuan-Hung; Cohen-Berros, Eva; Troxler, Laurent; Batsche, Eric; Camonis, Jacques; Takeuchi, Osamu; Reichhart, Jean-Marc; Matt, Nicolas

    2014-01-01

    The network of NF-κB-dependent transcription that activates both pro- and anti-inflammatory genes in mammals is still unclear. As NF-κB factors are evolutionarily conserved, we used Drosophila to understand this network. The NF-κB transcription factor Relish activates effector gene expression following Gram-negative bacterial immune challenge. Here, we show, using a genome-wide approach, that the conserved nuclear protein Akirin is a NF-κB co-factor required for the activation of a subset of Relish-dependent genes correlating with the presence of H3K4ac epigenetic marks. A large-scale unbiased proteomic analysis revealed that Akirin orchestrates NF-κB transcriptional selectivity through the recruitment of the Osa-containing-SWI/SNF-like Brahma complex (BAP). Immune challenge in Drosophila shows that Akirin is required for the transcription of a subset of effector genes, but dispensable for the transcription of genes that are negative regulators of the innate immune response. Therefore, Akirins act as molecular selectors specifying the choice between subsets of NF-κB target genes. The discovery of this mechanism, conserved in mammals, paves the way for the establishment of more specific and less toxic anti-inflammatory drugs targeting pro-inflammatory genes. PMID:25180232

  1. Akirin specifies NF-κB selectivity of Drosophila innate immune response via chromatin remodeling.

    PubMed

    Bonnay, François; Nguyen, Xuan-Hung; Cohen-Berros, Eva; Troxler, Laurent; Batsche, Eric; Camonis, Jacques; Takeuchi, Osamu; Reichhart, Jean-Marc; Matt, Nicolas

    2014-10-16

    The network of NF-κB-dependent transcription that activates both pro- and anti-inflammatory genes in mammals is still unclear. As NF-κB factors are evolutionarily conserved, we used Drosophila to understand this network. The NF-κB transcription factor Relish activates effector gene expression following Gram-negative bacterial immune challenge. Here, we show, using a genome-wide approach, that the conserved nuclear protein Akirin is a NF-κB co-factor required for the activation of a subset of Relish-dependent genes correlating with the presence of H3K4ac epigenetic marks. A large-scale unbiased proteomic analysis revealed that Akirin orchestrates NF-κB transcriptional selectivity through the recruitment of the Osa-containing-SWI/SNF-like Brahma complex (BAP). Immune challenge in Drosophila shows that Akirin is required for the transcription of a subset of effector genes, but dispensable for the transcription of genes that are negative regulators of the innate immune response. Therefore, Akirins act as molecular selectors specifying the choice between subsets of NF-κB target genes. The discovery of this mechanism, conserved in mammals, paves the way for the establishment of more specific and less toxic anti-inflammatory drugs targeting pro-inflammatory genes.

  2. TRIM5 Retroviral Restriction Activity Correlates with the Ability To Induce Innate Immune Signaling

    PubMed Central

    Lascano, Josefina; Uchil, Pradeep D.; Mothes, Walther

    2015-01-01

    biology. TRIM5 is a cellular protein that protects host genome integrity by disrupting the retroviral capsid as it transports viral nucleic acid to the host cell nucleus. Previous data suggest that innate immune signaling contributes to TRIM5-mediated restriction. Here, we show that activation of innate immune signaling is conserved among primate and carnivore TRIM5 orthologues and among 3 of the 7 mouse Trim5 homologues and that such activity is required for TRIM5-mediated restriction activity. PMID:26468522

  3. Structural recognition and functional activation of Fc[gamma]R by innate pentraxins

    SciTech Connect

    Lu, Jinghua; Marnell, Lorraine L.; Marjon, Kristopher D.; Mold, Carolyn; Du Clos, Terry W.; Sun, Peter D.

    2009-10-05

    Pentraxins are a family of ancient innate immune mediators conserved throughout evolution. The classical pentraxins include serum amyloid P component (SAP) and C-reactive protein, which are two of the acute-phase proteins synthesized in response to infection. Both recognize microbial pathogens and activate the classical complement pathway through C1q. More recently, members of the pentraxin family were found to interact with cell-surface Fc{gamma} receptors (Fc{gamma}R) and activate leukocyte-mediated phagocytosis. Here we describe the structural mechanism for pentraxin's binding to Fc{gamma}R and its functional activation of Fc{gamma}R-mediated phagocytosis and cytokine secretion. The complex structure between human SAP and Fc{gamma}RIIa reveals a diagonally bound receptor on each SAP pentamer with both D1 and D2 domains of the receptor contacting the ridge helices from two SAP subunits. The 1:1 stoichiometry between SAP and Fc{gamma}RIIa infers the requirement for multivalent pathogen binding for receptor aggregation. Mutational and binding studies show that pentraxins are diverse in their binding specificity for Fc{gamma}R isoforms but conserved in their recognition structure. The shared binding site for SAP and IgG results in competition for Fc{gamma}R binding and the inhibition of immune-complex-mediated phagocytosis by soluble pentraxins. These results establish antibody-like functions for pentraxins in the Fc{gamma}R pathway, suggest an evolutionary overlap between the innate and adaptive immune systems, and have new therapeutic implications for autoimmune diseases.

  4. The Role of Environmental Factors in Modulating Immune Responses in Early Life

    PubMed Central

    MacGillivray, Duncan M.; Kollmann, Tobias R.

    2014-01-01

    The concept of immunological memory stipulates that past exposures shape present immune function. These exposures include not only specific antigens impacting adaptive immune memory but also conserved pathogen or danger associated molecular patterns that mold innate immune responses for prolonged periods of time. It should thus not come as a surprise that there is a vast range of external or environmental factors that impact immunity. The importance of environmental factors modulating immunity is most readily recognized in early life, a period of rapidly changing environments. We here summarize available data on the role of environment shaping immune development and from it derive an overarching hypothesis relating the underlying molecular mechanisms and evolutionary principles involved. PMID:25309535

  5. Innate Immune Signaling Activated by MDR Bacteria in the Airway.

    PubMed

    Parker, Dane; Ahn, Danielle; Cohen, Taylor; Prince, Alice

    2016-01-01

    Health care-associated bacterial pneumonias due to multiple-drug resistant (MDR) pathogens are an important public health problem and are major causes of morbidity and mortality worldwide. In addition to antimicrobial resistance, these organisms have adapted to the milieu of the human airway and have acquired resistance to the innate immune clearance mechanisms that normally prevent pneumonia. Given the limited efficacy of antibiotics, bacterial clearance from the airway requires an effective immune response. Understanding how specific airway pathogens initiate and regulate innate immune signaling, and whether this response is excessive, leading to host-induced pathology may guide future immunomodulatory therapy. We will focus on three of the most important causes of health care-associated pneumonia, Staphylococcus aureus, Pseudomonas aeruginosa, and Klebsiella pneumoniae, and review the mechanisms through which an inappropriate or damaging innate immune response is stimulated, as well as describe how airway pathogens cause persistent infection by evading immune activation.

  6. Innate Immune Signaling Activated by MDR Bacteria in the Airway

    PubMed Central

    Parker, Dane; Ahn, Danielle; Cohen, Taylor; Prince, Alice

    2015-01-01

    Health care-associated bacterial pneumonias due to multiple-drug resistant (MDR) pathogens are an important public health problem and are major causes of morbidity and mortality worldwide. In addition to antimicrobial resistance, these organisms have adapted to the milieu of the human airway and have acquired resistance to the innate immune clearance mechanisms that normally prevent pneumonia. Given the limited efficacy of antibiotics, bacterial clearance from the airway requires an effective immune response. Understanding how specific airway pathogens initiate and regulate innate immune signaling, and whether this response is excessive, leading to host-induced pathology may guide future immunomodulatory therapy. We will focus on three of the most important causes of health care-associated pneumonia, Staphylococcus aureus, Pseudomonas aeruginosa, and Klebsiella pneumoniae, and review the mechanisms through which an inappropriate or damaging innate immune response is stimulated, as well as describe how airway pathogens cause persistent infection by evading immune activation. PMID:26582515

  7. The respiratory microbiome and innate immunity in asthma

    PubMed Central

    Huang, Yvonne J.

    2015-01-01

    Purpose of review The purpose of this study is to summarize recent studies of the lower respiratory microbiome in asthma, the role of innate immunity in asthma and strategies to understand complex microbiome–immune interactions in asthma. Recent findings Recent evidence indicates that the composition of lower respiratory microbiota in asthmatic individuals, across a spectrum of disease severity, is altered compared with healthy individuals. Attributes of this altered airway microbiome have been linked to clinical and inflammatory features of asthma. The importance of innate immune cells and mucosal defense systems in asthma is increasingly appreciated and may be dysregulated in the disease. Summary Interactions between the respiratory microbiome and innate mucosal immunity in asthma are complex and a challenge to dissect. Multiple avenues of investigation, leveraging a variety of methodologies, will need to be pursued to understand functional relationships to clinical and inflammatory phenotypes seen in asthma. PMID:25405668

  8. Innate immune mechanisms in vitiligo: danger from within.

    PubMed

    Richmond, Jillian M; Frisoli, Michael L; Harris, John E

    2013-12-01

    Vitiligo is an autoimmune disease of the skin in which melanocytes are destroyed by antigen-specific T cells, resulting in patchy depigmentation. Although adaptive immunity plays a clear role in disease progression, initiating factors are largely unknown. Many studies report that cellular stress pathways are dysregulated in melanocytes from vitiligo patients, suggesting that melanocyte-intrinsic defects participate in disease pathogenesis. Recent studies reveal that melanocyte stress generates damage-associated molecular patterns that activate innate immunity, thus connecting stress to organ-specific inflammation. Genetic studies in vitiligo support a role for stress, innate immunity, and adaptive mechanisms. Here, we discuss advances in the field that highlight how cellular stress, endogenous danger signals, and innate immune activation promote the onset of vitiligo.

  9. Group 2 innate lymphoid cells in the lung.

    PubMed

    Drake, Li Yin; Kita, Hirohito

    2014-01-01

    As the first line of defense, innate immunity plays an important role in protecting the host against pathogens. Innate lymphoid cells (ILCs) are emerging as important effector cells in the innate immune system and the cell type that regulate immune and tissue homeostases. Group 2 ILCs (ILC2s) are a subset of ILCs and are characterized by their capacity to produce large quantities of type 2 cytokines and certain tissue growth factors. In animal models, lung ILC2s are involved in allergic airway inflammation induced by exposure to allergens even in the absence of CD4(+) T cells and are likely responsible for tissue repair and recovery after respiratory virus infection. ILC2s are also identified in various organs in humans, and the numbers are increased in mucosal tissues from patients with allergic disorders. Further investigations of this novel cell type will provide major conceptual advances in our understanding of the mechanisms of asthma and allergic diseases.

  10. Retinoic Acid and Its Role in Modulating Intestinal Innate Immunity

    PubMed Central

    Czarnewski, Paulo; Das, Srustidhar; Parigi, Sara M.; Villablanca, Eduardo J.

    2017-01-01

    Vitamin A (VA) is amongst the most well characterized food-derived nutrients with diverse immune modulatory roles. Deficiency in dietary VA has not only been associated with immune dysfunctions in the gut, but also with several systemic immune disorders. In particular, VA metabolite all-trans retinoic acid (atRA) has been shown to be crucial in inducing gut tropism in lymphocytes and modulating T helper differentiation. In addition to the widely recognized role in adaptive immunity, increasing evidence identifies atRA as an important modulator of innate immune cells, such as tolerogenic dendritic cells (DCs) and innate lymphoid cells (ILCs). Here, we focus on the role of retinoic acid in differentiation, trafficking and the functions of innate immune cells in health and inflammation associated disorders. Lastly, we discuss the potential involvement of atRA during the plausible crosstalk between DCs and ILCs. PMID:28098786

  11. Probiotics promote gut health through stimulation of epithelial innate immunity.

    PubMed

    Pagnini, Cristiano; Saeed, Rubina; Bamias, Giorgos; Arseneau, Kristen O; Pizarro, Theresa T; Cominelli, Fabio

    2010-01-05

    Probiotic formulations are widely available and have a variety of proposed beneficial effects, including promotion of gut health. The mechanisms of action of probiotic bacteria in the intestine are still unclear but are generally attributed to an antiinflammatory effect. Here, we demonstrate that the multiple probiotic formulation VSL#3 prevents the onset of intestinal inflammation by local stimulation of epithelial innate immune responses (i.e., increased production of epithelial-derived TNF-alpha and restoration of epithelial barrier function in vivo). We also demonstrate that probiotic bacteria stimulate epithelial production of TNF-alpha and activate NF-kappaB in vitro. Our results support the hypothesis that probiotics promote gut health through stimulation, rather than suppression, of the innate immune system. Furthermore, our findings provide the perspective that defects in innate immunity may play a critical role in the pathogenesis and progression of intestinal disorders, such as inflammatory bowel disease.

  12. Innate immunity to mycobacteria: vitamin D and autophagy.

    PubMed

    Jo, Eun-Kyeong

    2010-08-01

    Autophagy is an ancient mechanism of protein degradation and a novel antimicrobial strategy. With respect to host defences against mycobacteria, autophagy plays a crucial role in antimycobacterial resistance, and contributes to immune surveillance of intracellular pathogens and vaccine efficacy. Vitamin D3 contributes to host immune responses against Mycobacterium tuberculosis through LL-37/hCAP-18, which is the only cathelicidin identified to date in humans. In this review, we discuss recent advances in our understanding of host immune strategies against mycobacteria, including vitamin D-mediated innate immunity and autophagy activation. This review also addresses our current understanding regarding the autophagy connection to principal innate machinery, such as ubiquitin- or inflammasome-involved pathways. Integrated dialog between autophagy and innate immunity may contribute to adequate host immune defences against mycobacterial infection.

  13. Molecular Profiling of Phagocytic Immune Cells in Anopheles gambiae Reveals Integral Roles for Hemocytes in Mosquito Innate Immunity.

    PubMed

    Smith, Ryan C; King, Jonas G; Tao, Dingyin; Zeleznik, Oana A; Brando, Clara; Thallinger, Gerhard G; Dinglasan, Rhoel R

    2016-11-01

    The innate immune response is highly conserved across all eukaryotes and has been studied in great detail in several model organisms. Hemocytes, the primary immune cell population in mosquitoes, are important components of the mosquito innate immune response, yet critical aspects of their biology have remained uncharacterized. Using a novel method of enrichment, we isolated phagocytic granulocytes and quantified their proteomes by mass spectrometry. The data demonstrate that phagocytosis, blood-feeding, and Plasmodium falciparum infection promote dramatic shifts in the proteomic profiles of An. gambiae granulocyte populations. Of interest, large numbers of immune proteins were induced in response to blood feeding alone, suggesting that granulocytes have an integral role in priming the mosquito immune system for pathogen challenge. In addition, we identify several granulocyte proteins with putative roles as membrane receptors, cell signaling, or immune components that when silenced, have either positive or negative effects on malaria parasite survival. Integrating existing hemocyte transcriptional profiles, we also compare differences in hemocyte transcript and protein expression to provide new insight into hemocyte gene regulation and discuss the potential that post-transcriptional regulation may be an important component of hemocyte gene expression. These data represent a significant advancement in mosquito hemocyte biology, providing the first comprehensive proteomic profiling of mosquito phagocytic granulocytes during homeostasis blood-feeding, and pathogen challenge. Together, these findings extend current knowledge to further illustrate the importance of hemocytes in shaping mosquito innate immunity and their principal role in defining malaria parasite survival in the mosquito host.

  14. Evolution of Innate Immunity: Clues from Invertebrates via Fish to Mammals.

    PubMed

    Buchmann, Kurt

    2014-01-01

    Host responses against invading pathogens are basic physiological reactions of all living organisms. Since the appearance of the first eukaryotic cells, a series of defense mechanisms have evolved in order to secure cellular integrity, homeostasis, and survival of the host. Invertebrates, ranging from protozoans to metazoans, possess cellular receptors, which bind to foreign elements and differentiate self from non-self. This ability is in multicellular animals associated with presence of phagocytes, bearing different names (amebocytes, hemocytes, coelomocytes) in various groups including animal sponges, worms, cnidarians, mollusks, crustaceans, chelicerates, insects, and echinoderms (sea stars and urchins). Basically, these cells have a macrophage-like appearance and function and the repair and/or fight functions associated with these cells are prominent even at the earliest evolutionary stage. The cells possess pathogen recognition receptors recognizing pathogen-associated molecular patterns, which are well-conserved molecular structures expressed by various pathogens (virus, bacteria, fungi, protozoans, helminths). Scavenger receptors, Toll-like receptors, and Nod-like receptors (NLRs) are prominent representatives within this group of host receptors. Following receptor-ligand binding, signal transduction initiates a complex cascade of cellular reactions, which lead to production of one or more of a wide array of effector molecules. Cytokines take part in this orchestration of responses even in lower invertebrates, which eventually may result in elimination or inactivation of the intruder. Important innate effector molecules are oxygen and nitrogen species, antimicrobial peptides, lectins, fibrinogen-related peptides, leucine rich repeats (LRRs), pentraxins, and complement-related proteins. Echinoderms represent the most developed invertebrates and the bridge leading to the primitive chordates, cephalochordates, and urochordates, in which many autologous genes

  15. Evolution of Innate Immunity: Clues from Invertebrates via Fish to Mammals

    PubMed Central

    Buchmann, Kurt

    2014-01-01

    Host responses against invading pathogens are basic physiological reactions of all living organisms. Since the appearance of the first eukaryotic cells, a series of defense mechanisms have evolved in order to secure cellular integrity, homeostasis, and survival of the host. Invertebrates, ranging from protozoans to metazoans, possess cellular receptors, which bind to foreign elements and differentiate self from non-self. This ability is in multicellular animals associated with presence of phagocytes, bearing different names (amebocytes, hemocytes, coelomocytes) in various groups including animal sponges, worms, cnidarians, mollusks, crustaceans, chelicerates, insects, and echinoderms (sea stars and urchins). Basically, these cells have a macrophage-like appearance and function and the repair and/or fight functions associated with these cells are prominent even at the earliest evolutionary stage. The cells possess pathogen recognition receptors recognizing pathogen-associated molecular patterns, which are well-conserved molecular structures expressed by various pathogens (virus, bacteria, fungi, protozoans, helminths). Scavenger receptors, Toll-like receptors, and Nod-like receptors (NLRs) are prominent representatives within this group of host receptors. Following receptor–ligand binding, signal transduction initiates a complex cascade of cellular reactions, which lead to production of one or more of a wide array of effector molecules. Cytokines take part in this orchestration of responses even in lower invertebrates, which eventually may result in elimination or inactivation of the intruder. Important innate effector molecules are oxygen and nitrogen species, antimicrobial peptides, lectins, fibrinogen-related peptides, leucine rich repeats (LRRs), pentraxins, and complement-related proteins. Echinoderms represent the most developed invertebrates and the bridge leading to the primitive chordates, cephalochordates, and urochordates, in which many autologous genes

  16. Dengue and soluble mediators of the innate immune system.

    PubMed

    Espada-Murao, Lyre Anni; Morita, Kouichi

    2011-12-01

    Huge emphasis has been placed on the role of the adaptive immune system in dengue pathogenesis. Yet there is increasing evidence for the importance of the innate immune system in regulating dengue infection and possibly influencing the disease. This review focuses on the interplay between the innate immune system and dengue and highlights the role of soluble immunological mediators. Type I and type II interferons of the innate immune system demonstrate non-overlapping roles in dengue infection. Furthermore, while some IFN responses to dengue are protective, others may exert disease-related effects on the host. But aside from interferons, a number of cytokines have also been implicated in dengue pathogenesis. Our expanding knowledge of cytokines indicates that these soluble mediators act upon a complicated network of events to provoke the disease. This cytokine storm is generally attributed to massive T cell activation as an outcome of secondary infection. However, there is reason to believe that innate immune response-derived cytokines also have contributory effects, especially in the context of severe cases of primary dengue infection. Another less popular but interesting perspective on dengue pathogenesis is the effect of mosquito feeding on host immune responses and viral infection. Various studies have shown that soluble factors from vector saliva have the capacity to alter immune reactions and thereby influence pathogen transmission and establishment. Hence, modulation of the innate immune system at various levels of infection is a critical component of dengue disease. In the absence of an approved drug or vaccine for dengue, soluble mediators of the innate immune system could be a strategic foothold for developing anti-viral therapeutics and improving clinical management.

  17. Innate immune control and regulation of influenza virus infections

    PubMed Central

    McGill, Jodi; Heusel, Jonathan W.; Legge, Kevin L.

    2009-01-01

    Adaptive immune responses are critical for the control and clearance of influenza A virus (IAV) infection. However, in recent years, it has become increasingly apparent that innate immune cells, including natural killer cells, alveolar macrophages (aMφ), and dendritic cells (DC) are essential following IAV infection in the direct control of viral replication or in the induction and regulation of virus-specific adaptive immune responses. This review will discuss the role of these innate immune cells following IAV infection, with a particular focus on DC and their ability to induce and regulate the adaptive IAV-specific immune response. PMID:19643736

  18. Knowing your friends: invertebrate innate immunity fosters beneficial bacterial symbioses

    PubMed Central

    Nyholm, Spencer V.; Graf, Joerg

    2013-01-01

    The innate immune system is present in all animals and is a crucial first line of defence against pathogens. However, animals also harbour large numbers of beneficial microorganisms that can be housed in the digestive tract, in specialized organs or on tissue surfaces. Although invertebrates lack conventional antibody-based immunity, they are capable of eliminating pathogens and, perhaps more importantly, discriminating them from other microorganisms. This Review examines the interactions between the innate immune systems of several model invertebrates and the symbionts of these organisms, and addresses the central question of how these long-lived and specific associations are established and maintained. PMID:23147708

  19. Bifidobacterium bifidum PRL2010 Modulates the Host Innate Immune Response

    PubMed Central

    Turroni, Francesca; Taverniti, Valentina; Ruas-Madiedo, Patricia; Duranti, Sabrina; Guglielmetti, Simone; Lugli, Gabriele Andrea; Gioiosa, Laura; Palanza, Paola; Margolles, Abelardo; van Sinderen, Douwe

    2014-01-01

    Here, we describe data obtained from transcriptome profiling of human cell lines and intestinal cells of a murine model upon exposure and colonization, respectively, with Bifidobacterium bifidum PRL2010. Significant changes were detected in the transcription of genes that are known to be involved in innate immunity. Furthermore, results from enzyme-linked immunosorbent assays (ELISAs) showed that exposure to B. bifidum PRL2010 causes enhanced production of interleukin 6 (IL-6) and IL-8 cytokines, presumably through NF-κB activation. The obtained global transcription profiles strongly suggest that Bifidobacterium bifidum PRL2010 modulates the innate immune response of the host. PMID:24242237

  20. Emerging Roles of Protein Deamidation in Innate Immune Signaling

    PubMed Central

    Zhao, Jun; Li, Junhua; Xu, Simin

    2016-01-01

    Protein deamidation has been considered a nonenzymatic process associated with protein functional decay or “aging.” Recent studies implicate protein deamidation in regulating signal transduction in fundamental biological processes, such as innate immune responses. Work investigating gammaherpesviruses and bacterial pathogens indicates that microbial pathogens deploy deamidases or enzyme-deficient homologues (pseudoenzymes) to induce deamidation of key signaling components and evade host immune responses. Here, we review studies on protein deamidation in innate immune signaling and present several imminent questions concerning the roles of protein deamidation in infection and immunity. PMID:26889032

  1. Inflammatory bowel disease related innate immunity and adaptive immunity.

    PubMed

    Huang, Yuan; Chen, Zhonge

    2016-01-01

    Inflammatory bowel disease (IBD) is a chronic nonspecific intestinal inflammatory disease, including ulcerative colitis (UC) and Crohn's disease (CD). Its pathogenesis remains not yet clear. Current researchers believe that after environmental factors act on individuals with genetic susceptibility, an abnormal intestinal immune response is launched under stimulation of intestinal flora. However, previous studies only focused on adaptive immunity in the pathogenesis of IBD. Currently, roles of innate immune response in the pathogenesis of intestinal inflammation have also drawn much attention. In this study, IBD related innate immunity and adaptive immunity were explained, especially the immune mechanisms in the pathogenesis of IBD.

  2. The Influence of Innate and Adaptive Immune Responses on Atherosclerosis

    PubMed Central

    Witztum, Joseph L.; Lichtman, Andrew H.

    2014-01-01

    Both the chronic development of atherosclerotic lesions and the acute changes in lesion phenotype that lead to clinical cardiovascular events are significantly influenced by the innate and adaptive immune responses to lipoprotein deposition and oxidation in the arterial wall. The rapid pace of discovery of mechanisms of immunologic recognition, effector functions, and regulation has significantly influenced the study of atherosclerosis, and our new knowledge is beginning to affect how we treat this ubiquitous disease. In this review, we discuss recent advances in our understanding of how innate and adaptive immunity contribute to atherosclerosis, as well as therapeutic opportunities that arise from this knowledge. PMID:23937439

  3. Beyond empiricism: informing vaccine development through innate immunity research.

    PubMed

    Levitz, Stuart M; Golenbock, Douglas T

    2012-03-16

    Although a great public heath success, vaccines provide suboptimal protection in some patient populations and are not available to protect against many infectious diseases. Insights from innate immunity research have led to a better understanding of how existing vaccines work and have informed vaccine development. New adjuvants and delivery systems are being designed based upon their capacity to stimulate innate immune sensors and target antigens to dendritic cells, the cells responsible for initiating adaptive immune responses. Incorporating these adjuvants and delivery systems in vaccines can beneficially alter the quantitative and qualitative nature of the adaptive immune response, resulting in enhanced protection.

  4. Comparative proteomic analysis reveals activation of mucosal innate immune signaling pathways during cholera.

    PubMed

    Ellis, Crystal N; LaRocque, Regina C; Uddin, Taher; Krastins, Bryan; Mayo-Smith, Leslie M; Sarracino, David; Karlsson, Elinor K; Rahman, Atiqur; Shirin, Tahmina; Bhuiyan, Taufiqur R; Chowdhury, Fahima; Khan, Ashraful Islam; Ryan, Edward T; Calderwood, Stephen B; Qadri, Firdausi; Harris, Jason B

    2015-03-01

    Vibrio cholerae O1 is a major cause of acute watery diarrhea in over 50 countries. Evidence suggests that V. cholerae O1 may activate inflammatory pathways, and a recent study of a Bangladeshi population showed that variants in innate immune genes play a role in mediating susceptibility to cholera. We analyzed human proteins present in the small intestine of patients infected with V. cholerae O1 to characterize the host response to this pathogen. We collected duodenal biopsy specimens from patients with acute cholera after stabilization and again 30 days after initial presentation. Peptides extracted from biopsy specimens were sequenced and quantified using label-free mass spectrometry and SEQUEST. Twenty-seven host proteins were differentially abundant between the acute and convalescent stages of infection; the majority of these have known roles in innate defense, cytokine production, and apoptosis. Immunostaining confirmed that two proteins, WARS and S100A8, were more abundant in lamina propria cells during the acute stage of cholera. Analysis of the differentially abundant proteins revealed the activation of key regulators of inflammation by the innate immune system, including Toll-like receptor 4, nuclear factor kappa-light-chain-enhancer of activated B cells, mitogen-activated protein kinases, and caspase-dependent inflammasomes. Interleukin-12β (IL-12β) was a regulator of several proteins that were activated during cholera, and we confirmed that IL-12β was produced by lymphocytes recovered from duodenal biopsy specimens of cholera patients. Our study shows that a broad inflammatory response is generated in the gut early after onset of cholera, which may be critical in the development of long-term mucosal immunity against V. cholerae O1.

  5. Salidroside exhibits anti-dengue virus activity by upregulating host innate immune factors.

    PubMed

    Sharma, Navita; Mishra, K P; Ganju, Lilly

    2016-12-01

    Dengue is an arboviral disease with no effective therapy available. Therefore, there is an urgent need to find a potent antiviral agent against dengue virus (DENV). In the present study, salidroside, a main bioactive compound of Rhodiola rosea, was evaluated for its antiviral potential against DENV serotype-2 infection and its effect on host innate immune factors. Antiviral effects of salidroside were examined in DENV-infected cells by western blotting, flow cytometry and real-time PCR. Its underlying mechanism involved in antiviral action was determined by evaluating expression of host innate immune factors including RIG-I, IRF-3, IRF-7, PKR, P-eIF2α and NF-κB. Salidroside potently inhibited DENV infection by decreasing DENV envelope protein expression more than tenfold. Salidroside exerts its antiviral activity by increasing expression of RNA helicases such as RIG-I, thereby initiating a downstream signaling cascade that induces upregulation of IRF-3 and IRF-7. It prevents viral protein synthesis by increasing the expression of PKR and P-eIF2α while decreasing NF-κB expression. It was also found to induce the expression of IFN-α. In addition, the number of NK cells and CD8(+) T cells were also found to be increased by salidroside treatment in human PBMCs, which are important in limiting DENV replication during early stages of infection. The findings presented here suggest that salidroside exhibits antiviral activity against DENV by inhibiting viral protein synthesis and boosting host immunity by increasing the expression of host innate immune factors and hence could be considered for the development of an effective therapeutic agent against DENV infection.

  6. Host Fate is Rapidly Determined by Innate Effector-Microbial Interactions During Acinetobacter baumannii Bacteremia

    PubMed Central

    Bruhn, Kevin W.; Pantapalangkoor, Paul; Nielsen, Travis; Tan, Brandon; Junus, Justin; Hujer, Kristine M.; Wright, Meredith S.; Bonomo, Robert A.; Adams, Mark D.; Chen, Wangxue; Spellberg, Brad

    2015-01-01

    Background. Acinetobacter baumannii is one of the most antibiotic-resistant pathogens. Defining mechanisms driving pathogenesis is critical to enable new therapeutic approaches. Methods. We studied virulence differences across a diverse panel of A. baumannii clinical isolates during murine bacteremia to elucidate host-microbe interactions that drive outcome. Results. We identified hypervirulent strains that were lethal at low intravenous inocula and achieved very high early, and persistent, blood bacterial densities. Virulent strains were nonlethal at low inocula but lethal at 2.5-fold higher inocula. Finally, relatively avirulent (hypovirulent) strains were nonlethal at 20-fold higher inocula and were efficiently cleared by early time points. In vivo virulence correlated with in vitro resistance to complement and macrophage uptake. Depletion of complement, macrophages, and neutrophils each independently increased bacterial density of the hypovirulent strain but insufficiently to change lethality. However, disruption of all 3 effector mechanisms enabled early bacterial densities similar to hypervirulent strains, rendering infection 100% fatal. Conclusions. The lethality of A. baumannii strains depends on distinct stages. Strains resistant to early innate effectors are able to establish very high early bacterial blood density, and subsequent sustained bacteremia leads to Toll-like receptor 4–mediated hyperinflammation and lethality. These results have important implications for translational efforts to develop therapies that modulate host-microbe interactions. PMID:25378635

  7. Rb selectively inhibits innate IFN-β production by enhancing deacetylation of IFN-β promoter through HDAC1 and HDAC8.

    PubMed

    Meng, Jun; Liu, Xingguang; Zhang, Peng; Li, Dong; Xu, Sheng; Zhou, Qingqing; Guo, Meng; Huai, Wanwan; Chen, Xiang; Wang, Quanxing; Li, Nan; Cao, Xuetao

    2016-09-01

    Type I IFN production is tightly controlled by host to generate efficient viral clearance without harmful immunopathology or induction of autoimmune disorders. Epigenetic regulation of type I IFN production in innate immunity and inflammatory disorders remains to be fully understood. Several tumor suppressors have been shown to regulate immune response and inflammation. However, the non-classical functions of tumor suppressors in innate immunity and inflammatory diseases need further identification. Here we report retinoblastoma protein (Rb) deficiency selectively enhanced TLR- and virus-triggered production of IFN-β which thus induced more IFN-α generation in the later phase of innate stimuli, but had no effect on the production of TNF, IL-6 and early phase IFN-α in macrophages. Rb1(fl/fl)Lyz2cre(+) Rb-deficient mice exhibited more resistant to lethal virus infection and more effective clearance of influenza virus. Rb selectively bound Ifnb1 enhancer region, but not the promoter of Ifna4, Tnf and Il6, by interacting with c-Jun, the component of IFN-β enhanceosome. Then Rb recruited HDAC1 and HDAC8 to attenuate acetylation of Histone H3/H4 in Ifnb1 promoter, resulting in suppression of Ifnb1 transcription. Therefore, Rb selectively inhibits innate IFN-β production by enhancing deacetylation of Ifnb1 promoter, exhibiting a previous unknown non-classical role in innate immunity, which also suggests a role of Rb in the regulation of type I IFN production in inflammatory or autoimmune diseases.

  8. Cultivating creativity in conservation science.

    PubMed

    Aslan, Clare E; Pinsky, Malin L; Ryan, Maureen E; Souther, Sara; Terrell, Kimberly A

    2014-04-01

    Conservation practitioners and scientists are often faced with seemingly intractable problems in which traditional approaches fail. While other sectors (e.g., business) frequently emphasize creative thinking to overcome complex challenges, creativity is rarely identified as an essential skill for conservationists. Yet more creative approaches are urgently needed in the effort to sustain Earth's biodiversity. We identified 4 strategies to develop skills in creative thinking and discuss underlying research and examples supporting each strategy. First, by breaking down barriers between disciplines and surrounding oneself with unfamiliar people, concepts, and perspectives, one can expand base knowledge and experiences and increase the potential for new combinations of ideas. Second, by meeting people where they are (both literally and figuratively), one exposes oneself to new environments and perspectives, which again broadens experiences and increases ability to communicate effectively with stakeholders. Third, by embracing risk responsibly, one is more likely to develop new, nontraditional solutions and be open to high-impact outcomes. Finally, by following a cycle of learning, struggle, and reflection, one can trigger neurophysiological changes that allow the brain to become more creative. Creativity is a learned trait, rather than an innate skill. It can be actively developed at both the individual and institutional levels, and learning to navigate the relevant social and practical barriers is key to the process. To maximize the success of conservation in the face of escalating challenges, one must take advantage of what has been learned from other disciplines and foster creativity as both a professional skill and an essential component of career training and individual development.

  9. Conservation potential of agricultural water conservation subsidies

    NASA Astrophysics Data System (ADS)

    Huffaker, Ray

    2008-07-01

    A current policy subsidizes farmers to invest in improved on-farm irrigation efficiency, expecting water to be conserved off farm. Contrary to expectation, water has been increasingly depleted in some regions after such improvements. This paper investigates the policy's failure to conserve water consistently by (1) formulating an economic model of irrigated crop production to determine a profit-maximizing irrigator's range of responses to a subsidy and (2) embedding these responses into hypothetical streamflow diagrams to ascertain their potential to conserve water under various hydrologic regimes. Testable hypotheses are developed to predict the conservation potential of a subsidy in real-world application.

  10. Zinc in innate and adaptive tumor immunity

    PubMed Central

    2010-01-01

    Zinc is important. It is the second most abundant trace metal with 2-4 grams in humans. It is an essential trace element, critical for cell growth, development and differentiation, DNA synthesis, RNA transcription, cell division, and cell activation. Zinc deficiency has adverse consequences during embryogenesis and early childhood development, particularly on immune functioning. It is essential in members of all enzyme classes, including over 300 signaling molecules and transcription factors. Free zinc in immune and tumor cells is regulated by 14 distinct zinc importers (ZIP) and transporters (ZNT1-8). Zinc depletion induces cell death via apoptosis (or necrosis if apoptotic pathways are blocked) while sufficient zinc levels allows maintenance of autophagy. Cancer cells have upregulated zinc importers, and frequently increased zinc levels, which allow them to survive. Based on this novel synthesis, approaches which locally regulate zinc levels to promote survival of immune cells and/or induce tumor apoptosis are in order. PMID:21087493

  11. NK Cells and Other Innate Lymphoid Cells in Hematopoietic Stem Cell Transplantation.

    PubMed

    Vacca, Paola; Montaldo, Elisa; Croxatto, Daniele; Moretta, Francesca; Bertaina, Alice; Vitale, Chiara; Locatelli, Franco; Mingari, Maria Cristina; Moretta, Lorenzo

    2016-01-01

    Natural killer (NK) cells play a major role in the T-cell depleted haploidentical hematopoietic stem cell transplantation (haplo-HSCT) to cure high-risk leukemias. NK cells belong to the expanding family of innate lymphoid cells (ILCs). At variance with NK cells, the other ILC populations (ILC1/2/3) are non-cytolytic, while they secrete different patterns of cytokines. ILCs provide host defenses against viruses, bacteria, and parasites, drive lymphoid organogenesis, and contribute to tissue remodeling. In haplo-HSCT patients, the extensive T-cell depletion is required to prevent graft-versus-host disease (GvHD) but increases risks of developing a wide range of life-threatening infections. However, these patients may rely on innate defenses that are reconstituted more rapidly than the adaptive ones. In this context, ILCs may represent important players in the early phases following transplantation. They may contribute to tissue homeostasis/remodeling and lymphoid tissue reconstitution. While the reconstitution of NK cell repertoire and its role in haplo-HSCT have been largely investigated, little information is available on ILCs. Of note, CD34(+) cells isolated from different sources of HSC may differentiate in vitro toward various ILC subsets. Moreover, cytokines released from leukemia blasts (e.g., IL-1β) may alter the proportions of NK cells and ILC3, suggesting the possibility that leukemia may skew the ILC repertoire. Further studies are required to define the timing of ILC development and their potential protective role after HSCT.

  12. INSIDE-OUT SIGNALING PATHWAYS FROM NUCLEAR ROS CONTROL PULMONARY INNATE IMMUNITY

    PubMed Central

    Choudhary, Sanjeev; Brasier, Allan R.

    2016-01-01

    The airway mucosa is responsible for mounting a robust innate immune response (IIR) upon encountering pathogen-associated molecular patterns. The IIR produces protective gene networks that stimulate neighboring epithelia and components of the immune system to trigger adaptive immunity. Little is currently known about how cellular reactive oxygen species (ROS) signaling is produced and cooperates in the IIR. We discuss recent discoveries on two nuclear ROS signaling pathways controlling innate immunity. Nuclear ROS oxidize guanine bases to produce mutagenic 8-oxoguanine, a lesion excised by 8-oxoguanine DNA glycosylase1/AP-lyase (OGG1). OGG1 forms a complex with the excised base, inducing its nuclear export. The cytoplasmic OGG1•8-oxoG complex functions as a guanine nucleotide exchange factor, triggering small GTPase signaling and activating phosphorylation of the NFκB/RelA transcription factor to induce immediate early gene expression. In parallel, nuclear ROS are detected by ataxia telangiectasia mutated (ATM), a PI3 kinase activated by ROS, triggering its nuclear export. ATM forms a scaffold with ribosomal S6 kinases, inducing RelA phosphorylation and resulting in transcription-coupled synthesis of type -I and –III interferons and CC and CXC chemokines. We propose that ATM and OGG1 are endogenous nuclear ROS sensors that transmit nuclear signals that coordinate with outside-in PRR signaling, regulating the IIR. PMID:26756522

  13. Developmental maturation of innate immune cell function correlates with susceptibility to central nervous system autoimmunity.

    PubMed

    Hertzenberg, Deetje; Lehmann-Horn, Klaus; Kinzel, Silke; Husterer, Veronika; Cravens, Petra D; Kieseier, Bernd C; Hemmer, Bernhard; Brück, Wolfgang; Zamvil, Scott S; Stüve, Olaf; Weber, Martin S

    2013-08-01

    MS is an inflammatory CNS disorder, which typically occurs in early adulthood and rarely in children. Here we tested whether functional maturation of innate immune cells may determine susceptibility to CNS autoimmune disease in EAE. Two-week-old mice were resistant to active EAE, which causes fulminant paralysis in adult mice; this resistance was associated with an impaired development of Th1 and Th17 cells. Resistant, young mice had higher frequencies of myeloid-derived suppressor cells and plasma-cytoid DCs. Furthermore, myeloid APCs and B cells from young mice expressed lower levels of MHC class II and CD40, produced decreased amounts of proinflammatory cytokines, and released enhanced levels of anti-inflammatory IL-10. When used as APCs, splenocytes from 2-week-old mice failed to differentiate naive T cells into Th1 and Th17 cells irrespective of the T-cell donor's age, and promoted development of Treg cells and Th2 cells instead. Adoptive transfer of adult APCs restored the ability of 2-week-old mice to generate encephalitogenic T cells and develop EAE. Collectively, these findings indicate that the innate immune compartment functionally matures during development, which may be a prerequisite for development of T-cell-mediated CNS autoimmune disease.

  14. Dissociation of Innate Immune Responses in Microglia Infected with Listeria monocytogenes

    PubMed Central

    Frande-Cabanes, Elisabet; Fernandez-Prieto, Lorena; Calderon-Gonzalez, Ricardo; Rodríguez-Del Río, Estela; Yañez-Diaz, Sonsoles; López-Fanarraga, Monica; Alvarez-Domínguez, Carmen

    2014-01-01

    Microglia, the innate immune cells of the brain, plays a central role in cerebral listeriosis. Here, we present evidence that microglia control Listeria infection differently than macrophages. Infection of primary microglial cultures and murine cell lines with Listeria resulted in a dual function of the two gene expression programmes involved in early and late immune responses in macrophages. Whereas the bacterial gene hly seems responsible for both transcriptional programmes in macrophages, Listeria induces in microglia only the tumor necrosis factor (TNF)-regulated transcriptional programme. Listeria also represses in microglia the late immune response gathered in two clusters, microbial degradation, and interferon (IFN)-inducible genes. The bacterial gene actA was required in microglia to induce TNF-regulated responses and to repress the late response. Isolation of microglial phagosomes revealed a phagosomal environment unable to destroy Listeria. Microglial phagosomes were also defective in several signaling and trafficking components reported as relevant for Listeria innate immune responses. This transcriptional strategy in microglia induced high levels of TNF-α and monocyte chemotactic protein-1 and low production of other neurotoxic compounds such as nitric oxide, hydrogen peroxide, and Type I IFNs. These cytokines and toxic microglial products are also released by primary microglia, and this cytokine and chemokine cocktail display a low potential to trigger neuronal apoptosis. This overall bacterial strategy strongly suggests that microglia limit Listeria inflammation pattern exclusively through TNF-mediated responses to preserve brain integrity. GLIA 2014;62:233–246 PMID:24311463

  15. Development of human natural killer cells and other innate lymphoid cells.

    PubMed

    Montaldo, Elisa; Vacca, Paola; Moretta, Lorenzo; Mingari, Maria Cristina

    2014-04-01

    Innate lymphoid cells (ILC) have recently gained much attention in immunology. They represent a novel developmentally related family. Three distinct subsets have been identified on the basis of phenotypic and functional criteria and termed ILC1, ILC2, and ILC3. The available data suggest that ILC play an important role in innate defenses against different pathogens, in lymphoid organogenesis, and in tissue remodeling. All these aspects are relevant in hematopoietic stem cell transplantation (HSCT), particularly in the haplo-HSCT setting, in which donor NK cells are known to play a major therapeutic role, while the involvement of other ILC is still undefined. In this context, it has been postulated that all ILC share a common precursor expressing the ID2 transcription factor. While the differentiation of human NK cells (belonging to ILC1) is now well characterized both in vitro and in vivo, limited information is available on the development of human ILC2 and ILC3 and of their relationships with NK cells. In this review, we will summarize the present knowledge on the developmental relationship among different ILC, with particular focus on early stages of NK cell differentiation, and their features shared with ILC2 and ILC3.

  16. ATM kinase inhibition in glial cells activates the innate immune response and causes neurodegeneration in Drosophila.

    PubMed

    Petersen, Andrew J; Rimkus, Stacey A; Wassarman, David A

    2012-03-13

    To investigate the mechanistic basis for central nervous system (CNS) neurodegeneration in the disease ataxia-telangiectasia (A-T), we analyzed flies mutant for the causative gene A-T mutated (ATM). ATM encodes a protein kinase that functions to monitor the genomic integrity of cells and control cell cycle, DNA repair, and apoptosis programs. Mutation of the C-terminal amino acid in Drosophila ATM inhibited the kinase activity and caused neuron and glial cell death in the adult brain and a reduction in mobility and longevity. These data indicate that reduced ATM kinase activity is sufficient to cause neurodegeneration in A-T. ATM kinase mutant flies also had elevated expression of innate immune response genes in glial cells. ATM knockdown in glial cells, but not neurons, was sufficient to cause neuron and glial cell death, a reduction in mobility and longevity, and elevated expression of innate immune response genes in glial cells, indicating that a non-cell-autonomous mechanism contributes to neurodegeneration in A-T. Taken together, these data suggest that early-onset CNS neurodegeneration in A-T is similar to late-onset CNS neurodegeneration in diseases such as Alzheimer's in which uncontrolled inflammatory response mediated by glial cells drives neurodegeneration.

  17. Gata3 drives development of RORγt+ group 3 innate lymphoid cells

    PubMed Central

    Serafini, Nicolas; Klein Wolterink, Roel G.J.; Satoh-Takayama, Naoko; Xu, Wei; Vosshenrich, Christian A.J.; Hendriks, Rudi W.

    2014-01-01

    Group 3 innate lymphoid cells (ILC3) include IL-22–producing NKp46+ cells and IL-17A/IL-22–producing CD4+ lymphoid tissue inducerlike cells that express RORγt and are implicated in protective immunity at mucosal surfaces. Whereas the transcription factor Gata3 is essential for T cell and ILC2 development from hematopoietic stem cells (HSCs) and for IL-5 and IL-13 production by T cells and ILC2, the role for Gata3 in the generation or function of other ILC subsets is not known. We found that abundant GATA-3 protein is expressed in mucosa-associated ILC3 subsets with levels intermediate between mature B cells and ILC2. Chimeric mice generated with Gata3-deficient fetal liver hematopoietic precursors lack all intestinal RORγt+ ILC3 subsets, and these mice show defective production of IL-22 early after infection with the intestinal pathogen Citrobacter rodentium, leading to impaired survival. Further analyses demonstrated that ILC3 development requires cell-intrinsic Gata3 expression in fetal liver hematopoietic precursors. Our results demonstrate that Gata3 plays a generalized role in ILC lineage determination and is critical for the development of gut RORγt+ ILC3 subsets that maintain mucosal barrier homeostasis. These results further extend the paradigm of Gata3-dependent regulation of diversified innate ILC and adaptive T cell subsets. PMID:24419270

  18. Metainflammation in Diabetic Coronary Artery Disease: Emerging Role of Innate and Adaptive Immune Responses

    PubMed Central

    Madhumitha, Haridoss

    2016-01-01

    Globally, noncommunicable chronic diseases such as Type-2 Diabetes Mellitus (T2DM) and Coronary Artery Disease (CAD) are posing a major threat to the world. T2DM is known to potentiate CAD which had led to the coining of a new clinical entity named diabetic CAD (DM-CAD), leading to excessive morbidity and mortality. The synergistic interaction between these two comorbidities is through sterile inflammation which is now being addressed as metabolic inflammation or metainflammation, which plays a pivotal role during both early and late stages of T2DM and also serves as a link between T2DM and CAD. This review summarises the current concepts on the role played by both innate and adaptive immune responses in setting up metainflammation in DM-CAD. More specifically, the role played by innate pattern recognition receptors (PRRs) like Toll-like receptors (TLRs), NOD1-like receptors (NLRs), Rig-1-like receptors (RLRs), and C-type lectin like receptors (CLRs) and metabolic endotoxemia in fuelling metainflammation in DM-CAD would be discussed. Further, the role played by adaptive immune cells (Th1, Th2, Th17, and Th9 cells) in fuelling metainflammation in DM-CAD will also be discussed. PMID:27610390

  19. Borrelia burgdorferi clinical isolates induce human innate immune responses that are not dependent on genotype.

    PubMed

    Mason, Lauren M K; Herkes, Eduard A; Krupna-Gaylord, Michelle A; Oei, Anneke; van der Poll, Tom; Wormser, Gary P; Schwartz, Ira; Petzke, Mary M; Hovius, Joppe W R

    2015-10-01

    Borrelia burgdorferi can be categorized based on restriction fragment length polymorphism analysis into ribosomal spacer type (RST) 1, 2 and 3. A correlation between RST type and invasiveness of Borrelia isolates has been demonstrated in clinical studies and experimental models, and RST 1 isolates are more likely to cause disseminated disease than RST 3 isolates. We hypothesized that this could partially be due to increased susceptibility of RST 3 isolates to killing by the innate immune system early in infection. Thus, we investigated the interaction of five RST 1 and five RST 3 isolates with various components of the human innate immune system in vitro. RST 3 isolates induced significantly greater upregulation of activation markers in monocyte-derived dendritic cells compared to RST 1 isolates at a low multiplicity of infection. However, RST 1 isolates stimulated greater interleukin-6 production. At a high multiplicity of infection no differences in dendritic cell activation or cytokine production were observed. In addition, we observed no differences in the ability of RST 1 and RST 3 isolates to activate monocytes or neutrophils and all strains were phagocytosed at a comparable rate. Finally, all isolates tested were equally resistant to complement-mediated killing, as determined by dark-field microscopy and a growth inhibition assay. In conclusion, we demonstrate that the RST 1 and 3 isolates showed no distinction in their susceptibility to the various components of the human immune system studied here, suggesting that other factors are responsible for their differential invasiveness.

  20. Viral evasion mechanisms of early antiviral responses involving regulation of ubiquitin pathways.

    PubMed

    Rajsbaum, Ricardo; García-Sastre, Adolfo

    2013-08-01

    Early innate and cell-intrinsic responses are essential to protect host cells against pathogens. In turn, viruses have developed sophisticated mechanisms to establish productive infections by counteracting host innate immune responses. Increasing evidence indicates that these antiviral factors may have a dual role by directly inhibiting viral replication as well as by sensing and transmitting signals to induce antiviral cytokines. Recent studies have pointed at new, unappreciated mechanisms of viral evasion of host innate protective responses including manipulating the host ubiquitin (Ub) system. Virus-mediated inhibition of antiviral factors by Ub-dependent degradation is emerging as a crucial mechanism for evading the antiviral response. In addition, recent studies have uncovered new mechanisms by which virus-encoded proteins inhibit Ub and Ub-like (Ubl) modification of host proteins involved in innate immune signaling pathways. Here we discuss recent findings and novel strategies that viruses have developed to counteract these early innate antiviral defenses.

  1. Innate immune responses of temperamental and calm cattle after transportation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The objective was to investigate measures of cellular innate immune responses among calm and temperamental Brahman bulls in response to handling and transportation. Sixteen Brahman bulls (344 ± 37 days of age; 271.6 ± 45.5 kg BW) classified as either calm (n = 8) or temperamental (n = 8) were loaded...

  2. Developmental acquisition of regulomes underlies innate lymphoid cell functionality

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Innate lymphoid cells (ILCs) play key roles in host defense, barrier integrity, and homeostasis, and they mirror adaptive CD4+ T helper (Th) cell subtypes in both usages of effector molecules and ·transcription factors. To better understand ILC subsets and their relationship with Th cells, we measur...

  3. Immune tolerance induction by integrating innate and adaptive immune regulators

    PubMed Central

    Suzuki, Jun; Ricordi, Camillo; Chen, Zhibin

    2009-01-01

    A diversity of immune tolerance mechanisms have evolved to protect normal tissues from immune damage. Immune regulatory cells are critical contributors to peripheral tolerance. These regulatory cells, exemplified by the CD4+Foxp3+ regulatory T (Treg) cells and a recently identified population named myeloid-derived suppressor cells (MDSCs), regulate immune responses and limiting immune-mediated pathology. In a chronic inflammatory setting, such as allograft-directed immunity, there may be a dynamic “crosstalk” between the innate and adaptive immunomodulatory mechanisms for an integrated control of immune damage. CTLA4-B7-based interaction between the two branches may function as a molecular “bridge” to facilitate such “crosstalk”. Understanding the interplays among Treg cells, innate suppressors and pathogenic effector T (Teff) cells will be critical in the future to assist in the development of therapeutic strategies to enhance and synergize physiological immunosuppressive elements in the innate and adaptive immune system. Successful development of localized strategies of regulatory cell therapies could circumvent the requirement for very high number of cells and decrease the risks associated with systemic immunosuppression. To realize the potential of innate and adaptive immune regulators for the still-elusive goal of immune tolerance induction, adoptive cell therapies may also need to be coupled with agents enhancing endogenous tolerance mechanisms. PMID:19919733

  4. RNA Editing, ADAR1, and the Innate Immune Response

    PubMed Central

    Wang, Qingde; Li, Xiaoni; Qi, Ruofan; Billiar, Timothy

    2017-01-01

    RNA editing, particularly A-to-I RNA editing, has been shown to play an essential role in mammalian embryonic development and tissue homeostasis, and is implicated in the pathogenesis of many diseases including skin pigmentation disorder, autoimmune and inflammatory tissue injury, neuron degeneration, and various malignancies. A-to-I RNA editing is carried out by a small group of enzymes, the adenosine deaminase acting on RNAs (ADARs). Only three members of this protein family, ADAR1–3, exist in mammalian cells. ADAR3 is a catalytically null enzyme and the most significant function of ADAR2 was found to be in editing on the neuron receptor GluR-B mRNA. ADAR1, however, has been shown to play more significant roles in biological and pathological conditions. Although there remains much that is not known about how ADAR1 regulates cellular function, recent findings point to regulation of the innate immune response as an important function of ADAR1. Without appropriate RNA editing by ADAR1, endogenous RNA transcripts stimulate cytosolic RNA sensing receptors and therefore activate the IFN-inducing signaling pathways. Overactivation of innate immune pathways can lead to tissue injury and dysfunction. However, obvious gaps in our knowledge persist as to how ADAR1 regulates innate immune responses through RNA editing. Here, we review critical findings from ADAR1 mechanistic studies focusing on its regulatory function in innate immune responses and identify some of the important unanswered questions in the field. PMID:28106799

  5. Endogenous opioid peptides in regulation of innate immunity cell functions.

    PubMed

    Gein, S V; Baeva, T A

    2011-03-01

    Endogenous opioid peptides comprise a group of bioregulatory factors involved in regulation of functional activity of various physiological systems of an organism. One of most important functions of endogenous opioids is their involvement in the interaction between cells of the nervous and immune systems. Summary data on the effects of opioid peptides on regulation of functions of innate immunity cells are presented.

  6. Thinking like a Scientist: Innateness as a Case Study

    ERIC Educational Resources Information Center

    Knobe, Joshua; Samuels, Richard

    2013-01-01

    The concept of innateness appears in systematic research within cognitive science, but it also appears in less systematic modes of thought that long predate the scientific study of the mind. The present studies therefore explore the relationship between the properly scientific uses of this concept and its role in ordinary folk understanding.…

  7. The immunobiology of Campylobacter jejuni: Innate immunity and autoimmune diseases.

    PubMed

    Phongsisay, Vongsavanh

    2016-04-01

    The Gram-negative bacterium Campylobacter jejuni causes gastroenteritis and Guillain-Barré syndrome in humans. Recent advances in the immunobiology of C. jejuni have been made. This review summarizes C. jejuni-binding innate receptors and highlights the role of innate immunity in autoimmune diseases. This human pathogen produces a variety of glycoconjugates, including human ganglioside-like determinants and multiple activators of Toll-like receptors (TLRs). Furthermore, C. jejuni targets MyD88, NLRP3 inflammasome, TIR-domain-containing adapter-inducing interferon-β (TRIF), sialic acid-binding immunoglobulin-like lectins (Siglecs), macrophage galactose-type lectin (MGL), and immunoglobulin-like receptors (TREM2, LMIR5/CD300b). The roles of these innate receptors and signaling molecules have been extensively studied. MyD88-mediated TLR activation or inflammasome-dependent IL-1β secretion is essential for autoimmune induction. TRIF mediates the production of type I interferons that promote humoral immune responses and immunoglobulin class-switching. Siglec-1 and Siglec-7 interact directly with gangliosides. Siglec-1 activation enhances phagocytosis and inflammatory responses. MGL internalizes GalNAc-containing glycoconjugates. TREM2 is well-known for its role in phagocytosis. LMIR5 recognizes C. jejuni components and endogenous sulfoglycolipids. Several lines of evidence from animal models of autoimmune diseases suggest that simultaneous activation of innate immunity in the presence of autoreactive lymphocytes or antigen mimicry may link C. jejuni to immunopathology.

  8. Innate immunity in the lung regulates the development of asthma.

    PubMed

    DeKruyff, Rosemarie H; Yu, Sanhong; Kim, Hye Young; Umetsu, Dale T

    2014-07-01

    The lung, while functioning as a gas exchange organ, encounters a large array of environmental factors, including particulate matter, toxins, reactive oxygen species, chemicals, allergens, and infectious microbes. To rapidly respond to and counteract these elements, a number of innate immune mechanisms have evolved that can lead to lung inflammation and asthma, which is the focus of this review. These innate mechanisms include a role for two incompletely understood cell types, invariant natural killer T (iNKT) cells and innate lymphoid cells (ILCs), which together produce a wide range of cytokines, including interleukin-4 (IL-4), IL-5, IL-13, interferon-γ, IL-17, and IL-22, independently of adaptive immunity and conventional antigens. The specific roles of iNKT cells and ILCs in immunity are still being defined, but both cell types appear to play important roles in the lungs, particularly in asthma. As we gain a better understanding of these innate cell types, we will acquire great insight into the mechanisms by which allergic and non-allergic asthma phenotypes develop.

  9. Health Realization: An Innate Resiliency Paradigm for School Psychology.

    ERIC Educational Resources Information Center

    Mills, Roger C.; Shuford, Rita

    This paper presents findings regarding the role of youth's moment to moment thinking and state of mind in determining perception. These findings, along with discoveries about innate resiliency and an understanding of the underlying principles that describe how thoughts become perception, have demonstrated efficacy in empowering youth to regain…

  10. Role of innate immunity in the pathogenesis of otitis media.

    PubMed

    Mittal, Rahul; Kodiyan, Joyson; Gerring, Robert; Mathee, Kalai; Li, Jian-Dong; Grati, M'hamed; Liu, Xue Zhong

    2014-12-01

    Otitis media (OM) is a public health problem in both developed and developing countries. It is the leading cause of hearing loss and represents a significant healthcare burden. In some cases, acute OM progresses to chronic suppurative OM (CSOM), characterized by effusion and discharge, despite antimicrobial therapy. The emergence of antibiotic resistance and potential ototoxicity of antibiotics has created an urgent need to design non-conventional therapeutic strategies against OM based on modern insights into its pathophysiology. In this article, we review the role of innate immunity as it pertains to OM and discuss recent advances in understanding the role of innate immune cells in protecting the middle ear. We also discuss the mechanisms utilized by pathogens to subvert innate immunity and thereby overcome defensive responses. A better knowledge about bacterial virulence and host resistance promises to reveal novel targets to design effective treatment strategies against OM. The identification and characterization of small natural compounds that can boost innate immunity may provide new avenues for the treatment of OM. There is also a need to design novel methods for targeted delivery of these compounds into the middle ear, allowing higher therapeutic doses and minimizing systemic side effects.

  11. Innate immune responses in hepatitis C virus infection.

    PubMed

    Li, Kui; Lemon, Stanley M

    2013-01-01

    Hepatitis C virus (HCV) is a major causative agent of chronic hepatitis and hepatocellular carcinoma worldwide and thus poses a significant public health threat. A hallmark of HCV infection is the extraordinary ability of the virus to persist in a majority of infected people. Innate immune responses represent the front line of defense of the human body against HCV immediately after infection. They also play a crucial role in orchestrating subsequent HCV-specific adaptive immunity that is pivotal for viral clearance. Accumulating evidence suggests that the host has evolved multifaceted innate immune mechanisms to sense HCV infection and elicit defense responses, while HCV has developed elaborate strategies to circumvent many of these. Defining the interplay of HCV with host innate immunity reveals mechanistic insights into hepatitis C pathogenesis and informs approaches to therapy. In this review, we summarize recent advances in understanding innate immune responses to HCV infection, focusing on induction and effector mechanisms of the interferon antiviral response as well as the evasion strategies of HCV.

  12. Mast cells as effector cells of innate immunity and regulators of adaptive immunity.

    PubMed

    Cardamone, Chiara; Parente, Roberta; Feo, Giulia De; Triggiani, Massimo

    2016-10-01

    Mast cells are widely distributed in human organs and tissues and they are particularly abundant at major body interfaces with the external environment such as the skin, the lung and the gastrointestinal tract. Moreover, mast cells are located around blood vessels and are highly represented within central and peripheral lymphoid organs. The strategic distribution of mast cells closely reflects the primary role of these cells in providing first-line defense against environmental dangers, in regulating local and systemic inflammatory reactions and in shaping innate and adaptive immune responses. Human mast cells have pleiotropic and multivalent functions that make them highly versatile cells able to rapidly adapt responses to microenvironmental changes. They express a wide variety of surface receptors including immunoglobulin receptors, pathogen-associated molecular pattern receptors and danger signal receptors. The abundance of these receptors makes mast cells unique and effective surveillance cells able to detect promptly aggression by viral, bacterial and parasitic agents. In addition, mast cells express multiple receptors for cytokines and chemokines that confer them the capacity of being recruited and activated at sites of inflammation. Once activated by immunological or nonimmunological stimuli mast cells secrete a wide spectrum of preformed (early) and de novo synthesized (late) mediators. Preformed mediators are stored within granules and are rapidly released in the extracellular environment to provide a fast vascular response that promotes inflammation and local recruitment of other innate immunity cells such as neutrophils, eosinophils, basophils and monocyte/macrophages. Later on, delayed release of multiple cytokines and chemokines from mast cells further induce modulation of cells of adaptive immunity and regulates tissue injury and, eventually, resolution of inflammation. Finally, mast cells express several costimulatory and inhibitory surface molecules

  13. Immunology primer for neurosurgeons and neurologists part 2: Innate brain immunity

    PubMed Central

    Blaylock, Russell L.

    2013-01-01

    evolves. For example, in the early stages of neurotrauma and stroke, microglia play a mostly neuroprotective role and only later switch to a neurodestructive mode. A great number of biological systems alter microglia function, including neurohormones, cannabinoids, other neurotransmitters, adenosine triphosphate (ATP), adenosine, and corticosteroids. One can appreciate that with aging many of these systems are altered by the aging process itself or by disease thus changing the sensitivity of the innate immune system. PMID:24083053

  14. Innate and guided C–H functionalization logic

    PubMed Central

    Brückl, Tobias; Baxter, Ryan D.; Ishihara, Yoshihiro; Baran, Phil S.

    2011-01-01

    Conspectus The combustion of organic matter is perhaps the oldest and most common chemical transformation utilized by mankind. The generation of a C–O bond at the expense of a C–H bond during this process may be considered the most basic form of C–H functionalization. This illustrates the extreme generality of the term ‘C–H functionalization,’ as it can describe the conversion of literally any C–H bond into a C–X bond (X being anything except H). Therefore, it may be of use to distinguish between what, in our view, are two distinct categories of C–H functionalization logic: ‘guided’ and ‘innate.’ Guided C–H functionalizations, as the name implies, are guided by external reagents or directing groups (covalently or fleetingly bound) to install new functional groups at the expense of specifically targeted C–H bonds. Conversely, innate C–H functionalizations may be broadly defined as reactions that exchange C–H bonds for new functional groups based solely on natural reactivity patterns in the absence of other directing forces. Two substrates that illustrate this distinction are dihydrojunenol and isonicotinic acid. The C–H functionalization processes of hydroxylation or arylation, respectively, can take place at multiple locations on each molecule. Innate functionalizations lead to substitution patterns that are dictated by the inherent bias (steric or electronic) of the substrate undergoing C–H cleavage, whereas guided functionalizations lead to substitution patterns that are controlled by external directing forces such as metal complexation or steric bias of the reagent. Although the distinction between guided and innate C–H functionalizations may not always be clear in cases that do not fit neatly into a single category, it is a useful convention to consider when analyzing reactivity patterns and strategies for synthesis. We must emphasize that although a completely rigorous distinction between guided and innate C

  15. Genetic control of the innate immune response

    PubMed Central

    Wells, Christine A; Ravasi, Timothy; Faulkner, Geoffrey J; Carninci, Piero; Okazaki, Yasushi; Hayashizaki, Yoshihide; Sweet, Matthew; Wainwright, Brandon J; Hume, David A

    2003-01-01

    Background Susceptibility to infectious diseases is directed, in part, by the interaction between the invading pathogen and host macrophages. This study examines the influence of genetic background on host-pathogen interactions, by assessing the transcriptional responses of macrophages from five inbred mouse strains to lipopolysaccharide (LPS), a major determinant of responses to gram-negative microorganisms. Results The mouse strains examined varied greatly in the number, amplitude and rate of induction of genes expressed in response to LPS. The response was attenuated in the C3H/HeJlpsd strain, which has a mutation in the LPS receptor Toll-like receptor 4 (TLR4). Variation between mouse strains allowed clustering into early (C57Bl/6J and DBA/2J) and delayed (BALB/c and C3H/ARC) transcriptional phenotypes. There was no clear correlation between gene induction patterns and variation at the Bcg locus (Slc11A1) or propensity to bias Th1 versus Th2 T cell activation responses. Conclusion Macrophages from each strain responded to LPS with unique gene expression profiles. The variation apparent between genetic backgrounds provides insights into the breadth of possible inflammatory responses, and paradoxically, this divergence was used to identify a common transcriptional program that responds to TLR4 signalling, irrespective of genetic background. Our data indicates that many additional genetic loci control the nature and the extent of transcriptional responses promoted by a single pathogen-associated molecular pattern (PAMP), such as LPS. PMID:12826024

  16. Integrating Early Writing into Science Instruction in Preschool

    ERIC Educational Resources Information Center

    Wheatley, Barbara C.; Gerde, Hope K.; Cabell, Sonia Q.

    2016-01-01

    Providing children with early writing opportunities in preschool is a meaningful way to facilitate their language and literacy learning. Young children have an innate curiosity of the natural world around them that motivates their learning; therefore science experiences are logical areas in which to incorporate early writing opportunities.…

  17. Cost-effectiveness of Early Surgery versus Conservative Treatment with Optional Delayed Meniscectomy for Patients over 45 years with non-obstructive meniscal tears (ESCAPE study): protocol of a randomised controlled trial

    PubMed Central

    van de Graaf, Victor A; Scholtes, Vanessa A B; Wolterbeek, Nienke; Noorduyn, Julia C A; Neeter, Camille; van Tulder, Maurits W; Saris, Daniël B F; de Gast, Arthur; Poolman, Rudolf W

    2016-01-01

    Introduction Recent studies show similar outcome between surgery and conservative treatment in patients with non-obstructive meniscal tears. However, surgery is still often preferred over conservative treatment. When conservative treatment is non-inferior to surgery, shifting the current standard treatment choice to conservative treatment alone could save over €30 millions of direct medical costs on an annual basis. Economic evaluation studies comparing surgery to conservative treatment are lacking. Methods and analysis A multicentre randomised controlled trial (RCT) with an economic evaluation alongside was performed to assess the (cost)-effectiveness of surgery and conservative treatment for meniscal tears. We will include 402 participants between 45 and 70 years with an MRI-confirmed symptomatic, non-obstructive meniscal tears to prove non-inferiority of conservative treatment. Block randomisation will be web-based. The primary outcome measure is a physical function, measured by the International Knee Documentation Committee ‘Subjective Knee Form’. Furthermore, we will perform a cost-effectiveness and cost-utility analysis from societal perspective and a budget impact analysis from a societal, government and insurer perspective. Secondary outcomes include general health, quality of life, activity level, knee pain, physical examination, progression of osteoarthritis and the occurrence of adverse events. Ethics and dissemination This RCT will be performed in accordance with the Declaration of Helsinki and has been approved by the Ethics Committee (number NL44188.100.13). The results of this study will be reported in peer-reviewed journals and at international conferences. We further aim to disseminate our results to guideline committees. Trial registration number NCT01850719. PMID:28003302

  18. Epithelium-Innate Immune Cell Axis in Mucosal Responses to SIV

    PubMed Central

    Shang, L.; Duan, L.; Perkey, K. E.; Wietgrefe, S.; Zupancic, M.; Smith, A. J.; Southern, P. J.; Johnson, R. P.; Haase, A. T.

    2016-01-01

    In the SIV-rhesus macaque model of HIV-1 transmission to women, one hallmark of the mucosal response to exposure to high doses of SIV is CD4 T cell recruitment that fuels local virus expansion in early infection. In this study, we systematically analyzed the cellular events and chemoattractant profiles in cervical tissues that precede CD4 T cell recruitment. We show that vaginal exposure to the SIV inoculum rapidly induces chemokine expression in cervical epithelium including CCL3, CCL20, and CXCL8. The chemokine expression is associated with early recruitment of macrophages and plasmacytoid dendritic cells that are co-clustered underneath the cervical epithelium. Production of chemokines CCL3 and CXCL8 by these cells in turn generates a chemokine gradient that is spatially correlated with the recruitment of CD4 T cells. We further show that the protection of SIVmac239Δnef vaccination against vaginal challenge is correlated with the absence of this epithelium-innate immune cell-CD4 T cell axis response in the cervical mucosa. Our results reveal a critical role for cervical epithelium in initiating early mucosal responses to vaginal infection, highlight an important role for macrophages in target cell recruitment and provide further evidence of a paradoxical dampening effect of a protective vaccine on these early mucosal responses. PMID:27435105

  19. Lactobacillus paraplantarum 11-1 Isolated from Rice Bran Pickles Activated Innate Immunity and Improved Survival in a Silkworm Bacterial Infection Model.

    PubMed

    Nishida, Satoshi; Ishii, Masaki; Nishiyama, Yayoi; Abe, Shigeru; Ono, Yasuo; Sekimizu, Kazuhisa

    2017-01-01

    Lactic acid bacteria (LAB) have high immune system-stimulating activity and are considered beneficial for human health as probiotics in the gut. The innate immune system is highly conserved between mammals and insects. Microbe-associated molecular patterns (e.g., peptidoglycan and β-glucan) induce cytokine maturation, which, in silkworm larvae, leads to muscle contraction. The purpose of this study is to find a novel probiotic by using silkworm muscle contraction assay. In the present study, we isolated LAB derived from rice bran pickles. We selected highly active LAB to activate the innate immune system of the silkworm, which was assayed based on silkworm muscle contraction. Of various LAB, L. paraplantarum 11-1 strongly stimulated innate immunity in the silkworm, leading to stronger silkworm contraction than a dairy-based LAB. Silkworms fed a diet containing L. paraplantarum 11-1 exhibited tolerance against the pathogenicity of Pseudomonas aeruginosa. These findings suggest that L. paraplantarum 11-1 could be a useful probiotic for activating innate immunity.

  20. Lactobacillus paraplantarum 11-1 Isolated from Rice Bran Pickles Activated Innate Immunity and Improved Survival in a Silkworm Bacterial Infection Model

    PubMed Central

    Nishida, Satoshi; Ishii, Masaki; Nishiyama, Yayoi; Abe, Shigeru; Ono, Yasuo; Sekimizu, Kazuhisa

    2017-01-01

    Lactic acid bacteria (LAB) have high immune system-stimulating activity and are considered beneficial for human health as probiotics in the gut. The innate immune system is highly conserved between mammals and insects. Microbe-associated molecular patterns (e.g., peptidoglycan and β-glucan) induce cytokine maturation, which, in silkworm larvae, leads to muscle contraction. The purpose of this study is to find a novel probiotic by using silkworm muscle contraction assay. In the present study, we isolated LAB derived from rice bran pickles. We selected highly active LAB to activate the innate immune system of the silkworm, which was assayed based on silkworm muscle contraction. Of various LAB, L. paraplantarum 11-1 strongly stimulated innate immunity in the silkworm, leading to stronger silkworm contraction than a dairy-based LAB. Silkworms fed a diet containing L. paraplantarum 11-1 exhibited tolerance against the pathogenicity of Pseudomonas aeruginosa. These findings suggest that L. paraplantarum 11-1 could be a useful probiotic for activating innate immunity. PMID:28373863

  1. The transcriptional regulator BZR1 mediates trade-off between plant innate immunity and growth

    PubMed Central

    Lozano-Durán, Rosa; Macho, Alberto P; Boutrot, Freddy; Segonzac, Cécile; Somssich, Imre E; Zipfel, Cyril

    2013-01-01

    The molecular mechanisms underlying the trade-off between plant innate immunity and steroid-mediated growth are controversial. Here, we report that activation of the transcription factor BZR1 is required and sufficient for suppression of immune signaling by brassinosteroids (BR). BZR1 induces the expression of several WRKY transcription factors that negatively control early immune responses. In addition, BZR1 associates with WRKY40 to mediate the antagonism between BR and immune signaling. We reveal that BZR1-mediated inhibition of immunity is particularly relevant when plant fast growth is required, such as during etiolation. Thus, BZR1 acts as an important regulator mediating the trade-off between growth and immunity upon integration of environmental cues. DOI: http://dx.doi.org/10.7554/eLife.00983.001 PMID:24381244

  2. The transcriptional regulator BZR1 mediates trade-off between plant innate immunity and growth.

    PubMed

    Lozano-Durán, Rosa; Macho, Alberto P; Boutrot, Freddy; Segonzac, Cécile; Somssich, Imre E; Zipfel, Cyril

    2013-12-31

    The molecular mechanisms underlying the trade-off between plant innate immunity and steroid-mediated growth are controversial. Here, we report that activation of the transcription factor BZR1 is required and sufficient for suppression of immune signaling by brassinosteroids (BR). BZR1 induces the expression of several WRKY transcription factors that negatively control early immune responses. In addition, BZR1 associates with WRKY40 to mediate the antagonism between BR and immune signaling. We reveal that BZR1-mediated inhibition of immunity is particularly relevant when plant fast growth is required, such as during etiolation. Thus, BZR1 acts as an important regulator mediating the trade-off between growth and immunity upon integration of environmental cues. DOI: http://dx.doi.org/10.7554/eLife.00983.001.

  3. [Escape mechanisms to the innate immune response in HPV-associated cervical cancer].

    PubMed

    del Toro-Arreola, Susana; García-Chagollán, Mariel; Jave-Suárez, Luis Felipe

    2015-01-01

    Cervical cancer is characterized by persistent human papilloma virus (HPV) infection. But, why, in some cases, is the immune system unable to reliably detect the HPV infection? For years, this has been a central question, which has yet to be fully answered. At present, it is well known that HPV has evolved a variety of mechanisms to evade the immune attack, and it is the success of these, which will be critical to determine whether the infection will be cleared or remain as a persistent infection. This review will be particularly focused on addressing some of the mechanisms used by HPV to avoid early recognition by the host innate immune system, which will then facilitate viral persistence with the consequent risk of eventual progression towards cervical cancer. Undoubtedly, an understanding of the balance between viral and immunological factors will provide crucial information that must to be taken into account for the design of prophylactic and therapeutic vaccines against HPV-associated cervical cancer.

  4. Cytokine Synergy: an underappreciated contributor to innate anti-viral immunity

    PubMed Central

    Bartee, Eric; McFadden, Grant

    2013-01-01

    Inflammatory cytokines, such as tumor necrosis factor and the members of the interferon family, are potent mediators of the innate anti-viral immune response. The intracellular anti-viral states resulting from treatment of cultured cells with each of these molecules independently has been well studied; but, within complex tissues, the early inflammatory response is likely mediated by simultaneously expressed mixures of these, and other, protective anti-viral cytokines. Such cytokine mixtures have been shown to induce potently synergistic anti-viral responses in vitro which are more complex than the simple summation of the individual cytokine response profiles. The physiological role of this ‘cytokine synergy’, however, remains largely unappreciated in vivo. This brief commentary will attempt to summarize the potential effects and mechanisms of anti-viral cytokine synergy as well as present several ‘real-world’ applications where this phenomenon might play an important role. PMID:23693158

  5. Innate immunity to RNA virus is regulated by temporal and reversible sumoylation of RIG-I and MDA5.

    PubMed

    Hu, Ming-Ming; Liao, Chen-Yang; Yang, Qing; Xie, Xue-Qin; Shu, Hong-Bing

    2017-04-03

    Sensing of viral RNA by the cytosolic receptors RIG-I and melanoma differentiation-associated gene 5 (MDA5) leads to innate antiviral response. How RIG-I and MDA5 are dynamically regulated in innate antiviral response is not well understood. Here, we show that TRIM38 positively regulates MDA5- and RIG-I-mediated induction of downstream genes and acts as a SUMO E3 ligase for their dynamic sumoylation at K43/K865 and K96/K888, respectively, before and after viral infection. The sumoylation of MDA5 and RIG-I suppresses their K48-linked polyubiquitination and degradation in uninfected or early-infected cells. Sumoylation of the caspase recruitment domains of MDA5 and RIG-I is also required for their dephosphorylation by PP1 and activation upon viral infection. At the late phase of viral infection, both MDA5 and RIG-I are desumoylated by SENP2, resulting in their K48-linked polyubiquitination and degradation. These findings suggest that dynamic sumoylation and desumoylation of MDA5 and RIG-I modulate efficient innate immunity to RNA virus and its timely termination.

  6. LIMP-2 Links Late Phagosomal Trafficking with the Onset of the Innate Immune Response to Listeria monocytogenes

    PubMed Central

    Carrasco-Marín, Eugenio; Fernández-Prieto, Lorena; Rodriguez-Del Rio, Estela; Madrazo-Toca, Fidel; Reinheckel, Thomas; Saftig, Paul; Alvarez-Dominguez, Carmen

    2011-01-01

    The innate immune response to Listeria monocytogenes depends on phagosomal bacterial degradation by macrophages. Here, we describe the role of LIMP-2, a lysosomal type III transmembrane glycoprotein and scavenger-like protein, in Listeria phagocytosis. LIMP-2-deficient mice display a macrophage-related defect in Listeria innate immunity. They produce less acute phase pro-inflammatory cytokines/chemokines, MCP-1, TNF-α, and IL-6 but normal levels of IL-12, IL-10, and IFN-γ and a 25-fold increase in susceptibility to Listeria infection. This macrophage defect results in a low listericidal potential, poor response to TNF-α activation signals, impaired phago-lysosome transformation into antigen-processing compartments, and uncontrolled LM cytosolic growth that fails to induce normal levels of acute phase pro-inflammatory cytokines. LIMP-2 transfection of CHO cells confirmed that LIMP-2 participates in the degradation of Listeria within phagosomes, controls the late endosomal/lysosomal fusion machinery, and is linked to the activation of Rab5a. Therefore, the role of LIMP-2 appears to be connected to the TNF-α-dependent and early activation of Listeria macrophages through internal signals linking the regulation of late trafficking events with the onset of the innate Listeria immune response. PMID:21123180

  7. Role of Innate Immunity against Human Papillomavirus (HPV) Infections and Effect of Adjuvants in Promoting Specific Immune Response

    PubMed Central

    Amador-Molina, Alfredo; Hernández-Valencia, José Fernando; Lamoyi, Edmundo; Contreras-Paredes, Adriana; Lizano, Marcela

    2013-01-01

    During the early stages of human papillomavirus (HPV) infections, the innate immune system creates a pro-inflammatory microenvironment by recruiting innate immune cells to eliminate the infected cells, initiating an effective acquired immune response. However, HPV exhibits a wide range of strategies for evading immune-surveillance, generating an anti-inflammatory microenvironment. The administration of new adjuvants, such as TLR (Toll-like receptors) agonists and alpha-galactosylceramide, has been demonstrated to reverse the anti-inflammatory microenvironment by down-regulating a number of adhesion molecules and chemo-attractants and activating keratinocytes, dendritic (DC), Langerhans (LC), natural killer (NK) or natural killer T (NKT) cells; thus, promoting a strong specific cytotoxic T cell response. Therefore, these adjuvants show promise for the treatment of HPV generated lesions and may be useful to elucidate the unknown roles of immune cells in the natural history of HPV infection. This review focuses on HPV immune evasion mechanisms and on the proposed response of the innate immune system, suggesting a role for the surrounding pro-inflammatory microenvironment and the NK and NKT cells in the clearance of HPV infections. PMID:24169630

  8. The Innate Immune Signaling System as a Regulator of Disease Resistance and Induced Systemic Resistance Activity Against Verticillium dahliae.

    PubMed

    Gkizi, Danai; Lehmann, Silke; L'Haridon, Floriane; Serrano, Mario; Paplomatas, Epaminondas J; Métraux, Jean-Pierre; Tjamos, Sotirios E

    2016-04-01

    In the last decades, the plant innate immune responses against pathogens have been extensively studied, while biocontrol interactions between soilborne fungal pathogens and their hosts have received much less attention. Treatment of Arabidopsis thaliana with the nonpathogenic bacterium Paenibacillus alvei K165 was shown previously to protect against Verticillium dahliae by triggering induced systemic resistance (ISR). In the present study, we evaluated the involvement of the innate immune response in the K165-mediated protection of Arabidopsis against V. dahliae. Tests with Arabidopsis mutants impaired in several regulators of the early steps of the innate immune responses, including fls2, efr-1, bak1-4, mpk3, mpk6, wrky22, and wrky29 showed that FLS2 and WRKY22 have a central role in the K165-triggered ISR, while EFR1, MPK3, and MPK6 are possible susceptibility factors for V. dahliae and bak1 shows a tolerance phenomenon. The resistance induced by strain K165 is dependent on both salicylate and jasmonate-dependent defense pathways, as evidenced by an increased transient accumulation of PR1 and PDF1.2 transcripts in the aerial parts of infected plants treated with strain K165.

  9. Conservation: Threatened by Luxury.

    PubMed

    Webb, Thomas J

    2016-06-20

    When animals are traded in lucrative international luxury markets, individuals really do matter to conservation. Identifying the intrinsic and extrinsic factors that make some species especially vulnerable to this kind of threat helps set guidelines for more effective conservation.

  10. Meeting global conservation challenges

    NASA Astrophysics Data System (ADS)

    2016-10-01

    Hot on the heels of last year's Sustainable Development Goals and the Paris Agreement, representatives from the global conservation community met to set the conservation agenda that will help to implement these targets.

  11. The impact of Aeromonas salmonicida infection on innate immune parameters of Atlantic salmon (Salmo salar L).

    PubMed

    Du, Yishuai; Yi, Mengmeng; Xiao, Peng; Meng, Lingjie; Li, Xian; Sun, Guoxiang; Liu, Ying

    2015-05-01

    Enzyme activities and gene expression of a number of innate immune parameters in the serum, mucus and skin of Atlantic salmon (Salmo salar) were investigated after challenge with a pathogenic strain of Aeromonas salmonicida (A. salmonicida). Fish were injected in the dorsal muscle with either 100 μl bacterium solution, about 3.05 × 10(7) CFU/ml A. salmonicida, or 100 μl 0.9% NaCl (as control group) and tissue samples were collected at days 0, 2, 4 and 6 post-injection. Lysozyme (LSZ) and alkaline phosphatase (AKP) activities in serum, mucus and skin, and LSZ and AKP mRNA expression in skin of the challenged fish were higher than those of the control at most of the experimental time, with significant differences at several time points (P < 0.05), indicating the involvement of LSZ and AKP in the innate immunity of Atlantic salmon to A. salmonicida. Superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT) activities in mucus and skin, along with the SOD, POD and CAT mRNA expression in skin significantly decreased at day 4 and 6, indicating the decreased antioxidant capacity of the challenged fish. Glutamate pyruvate transaminase (GPT) and glutamic oxalacetic transaminase (GOT) activities in serum, mucus and skin of the challenged group were all higher than those of the control after the injection, and at several time points significant differences were found between the two groups, suggesting organs of fish were impaired after the pathogen infection. The changes of the GPT and GOT activities could be used as potential biomarkers for the impairment of physiological functions caused by the pathogen infection. Identified biomarkers of the immune responses will contribute to the early-warning system of the disease. So this study will not only provide a theoretical basis for vaccine development, but also provide basic data for the establishment of early warning systems for diseases caused by A. salmonicida in Atlantic salmon rearing.

  12. Primate TNF Promoters Reveal Markers of Phylogeny and Evolution of Innate Immunity

    PubMed Central

    Baena, Andres; Ligeiro, Filipa; Diop, Ousmane M.; Brieva, Claudia; Gagneux, Pascal; O'Brien, Stephen J.; Ryder, Oliver A.; Goldfeld, Anne E.

    2007-01-01

    Background Tumor necrosis factor (TNF) is a critical cytokine in the immune response whose transcriptional activation is controlled by a proximal promoter region that is highly conserved in mammals and, in particular, primates. Specific single nucleotide polymorphisms (SNPs) upstream of the proximal human TNF promoter have been identified, which are markers of human ancestry. Methodology/Principal findings Using a comparative genomics approach we show that certain fixed genetic differences in the TNF promoter serve as markers of primate speciation. We also demonstrate that distinct alleles of most human TNF promoter SNPs are identical to fixed nucleotides in primate TNF promoters. Furthermore, we identify fixed genetic differences within the proximal TNF promoters of Asian apes that do not occur in African ape or human TNF promoters. Strikingly, protein-DNA binding assays and gene reporter assays comparing these Asian ape TNF promoters to African ape and human TNF promoters demonstrate that, unlike the fixed differences that we define that are associated with primate phylogeny, these Asian ape-specific fixed differences impair transcription factor binding at an Sp1 site and decrease TNF transcription induced by bacterial stimulation of macrophages. Conclusions/significance Here, we have presented the broadest interspecies comparison of a regulatory region of an innate immune response gene to date. We have characterized nucleotide positions in Asian ape TNF promoters that underlie functional changes in cell type- and stimulus-specific activation of the TNF gene. We have also identified ancestral TNF promoter nucleotide states in the primate lineage that correspond to human SNP alleles. These findings may reflect evolution of Asian and African apes under a distinct set of infectious disease pressures involving the innate immune response and TNF. PMID:17637837

  13. Building robust conservation plans.

    PubMed

    Visconti, Piero; Joppa, Lucas

    2015-04-01

    Systematic conservation planning optimizes trade-offs between biodiversity conservation and human activities by accounting for socioeconomic costs while aiming to achieve prescribed conservation objectives. However, the most cost-efficient conservation plan can be very dissimilar to any other plan achieving the set of conservation objectives. This is problematic under conditions of implementation uncertainty (e.g., if all or part of the plan becomes unattainable). We determined through simulations of parallel implementation of conservation plans and habitat loss the conditions under which optimal plans have limited chances of implementation and where implementation attempts would fail to meet objectives. We then devised a new, flexible method for identifying conservation priorities and scheduling conservation actions. This method entails generating a number of alternative plans, calculating the similarity in site composition among all plans, and selecting the plan with the highest density of neighboring plans in similarity space. We compared our method with the classic method that maximizes cost efficiency with synthetic and real data sets. When implementation was uncertain--a common reality--our method provided higher likelihood of achieving conservation targets. We found that χ, a measure of the shortfall in objectives achieved by a conservation plan if the plan could not be implemented entirely, was the main factor determining the relative performance of a flexibility enhanced approach to conservation prioritization. Our findings should help planning authorities prioritize conservation efforts in the face of uncertainty about future condition and availability of sites.

  14. Conservation in Physics.

    ERIC Educational Resources Information Center

    Finkel, Edward

    1991-01-01

    Discussed is the physical concept of conservation as it is framed within the laws of conservation of mass, of momentum, and of energy. The derivation of Ohm's Law as a generalization of the relationship between the observed measurements of voltage and current serves as the exemplar of how conservation theories are formed. (JJK)

  15. Conservation Action Handbook.

    ERIC Educational Resources Information Center

    National Rifle Association, Washington, DC.

    Conservation problems are identified, with some suggestions for action. General areas covered are: Wildlife Conservation, Soil Conservation, Clean Water, Air Pollution Action, and Outdoor Recreation Action. Appendices list private organizations or agencies concerned with natural resource use and/or management, congressional committees considering…

  16. ALV-J strain SCAU-HN06 induces innate immune responses in chicken primary monocyte-derived macrophages

    PubMed Central

    Feng, Min; Dai, Manman; Cao, Weisheng; Tan, Yan; Li, Zhenhui; Shi, Meiqing; Zhang, Xiquan

    2016-01-01

    Avian leucosis virus subgroup J (ALV-J) can cause lifelong infection and can escape from the host immune defenses in chickens. Since macrophages act as the important defense line against invading pathogens in host innate immunity, we investigated the function and innate immune responses of chicken primary monocyte-derived macrophages (MDM) after ALV-J infection in this study. Our results indicated that ALV-J was stably maintained in MDM cells but that the viral growth rate was significantly lower than that in DF-1 cells. We also found that ALV-J infection significantly increased nitric oxide (NO) production, but had no effect on MDM phagocytic capacity. Interestingly, infection with ALV-J rapidly promoted the expression levels of Myxovirus resistance 1 (Mx) (3 h, 6 h), ISG12 (6 h), and interleukin-1β (IL-1β) (3 h, 12 h) at an early infection stage, whereas it sharply decreased the expression of Mx (24 h, 36 h), ISG12 (36 h), and made little change on IL-1β (24 h, 36 h) production at a late infection stage in MDM cells. Moreover, the protein levels of interferon-β (IFN-β) and interleukin-6 (IL-6) had sharply increased in infected MDM cells from 3 to 36 h post infection (hpi) of ALV-J. And, the protein level of interleukin-10 (IL-10) was dramatically decreased at 36 hpi in MDM cells infected with ALV-J. These results demonstrate that ALV-J can induce host innate immune responses and we hypothesize that macrophages play an important role in host innate immune attack and ALV-J immune escape. PMID:27486255

  17. Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit(+)Sca-1(+) lymphoid cells.

    PubMed

    Moro, Kazuyo; Yamada, Taketo; Tanabe, Masanobu; Takeuchi, Tsutomu; Ikawa, Tomokatsu; Kawamoto, Hiroshi; Furusawa, Jun-Ichi; Ohtani, Masashi; Fujii, Hideki; Koyasu, Shigeo

    2010-01-28

    Innate immune responses are important in combating various microbes during the early phases of infection. Natural killer (NK) cells are innate lymphocytes that, unlike T and B lymphocytes, do not express antigen receptors but rapidly exhibit cytotoxic activities against virus-infected cells and produce various cytokines. Here we report a new type of innate lymphocyte present in a novel lymphoid structure associated with adipose tissues in the peritoneal cavity. These cells do not express lineage (Lin) markers but do express c-Kit, Sca-1 (also known as Ly6a), IL7R and IL33R. Similar lymphoid clusters were found in both human and mouse mesentery and we term this tissue 'FALC' (fat-associated lymphoid cluster). FALC Lin(-)c-Kit(+)Sca-1(+) cells are distinct from lymphoid progenitors and lymphoid tissue inducer cells. These cells proliferate in response to IL2 and produce large amounts of T(H)2 cytokines such as IL5, IL6 and IL13. IL5 and IL6 regulate B-cell antibody production and self-renewal of B1 cells. Indeed, FALC Lin(-)c-Kit(+)Sca-1(+) cells support the self-renewal of B1 cells and enhance IgA production. IL5 and IL13 mediate allergic inflammation and protection against helminth infection. After helminth infection and in response to IL33, FALC Lin(-)c-Kit(+)Sca-1(+) cells produce large amounts of IL13, which leads to goblet cell hyperplasia-a critical step for helminth expulsion. In mice devoid of FALC Lin(-)c-Kit(+)Sca-1(+) cells, such goblet cell hyperplasia was not induced. Thus, FALC Lin(-)c-Kit(+)Sca-1(+) cells are T(H)2-type innate lymphocytes, and we propose that these cells be called 'natural helper cells'.

  18. Synergy between Common γ Chain Family Cytokines and IL-18 Potentiates Innate and Adaptive Pathways of NK Cell Activation.

    PubMed

    Nielsen, Carolyn M; Wolf, Asia-Sophia; Goodier, Martin R; Riley, Eleanor M

    2016-01-01

    Studies to develop cell-based therapies for cancer and other diseases have consistently shown that purified human natural killer (NK) cells secrete cytokines and kill target cells after in vitro culture with high concentrations of cytokines. However, these assays poorly reflect the conditions that are likely to prevail in vivo in the early stages of an infection and have been carried out in a wide variety of experimental systems, which has led to contradictions within the literature. We have conducted a detailed kinetic and dose-response analysis of human NK cell responses to low concentrations of IL-12, IL-15, IL-18, IL-21, and IFN-α, alone and in combination, and their potential to synergize with IL-2. We find that very low concentrations of both innate and adaptive common γ chain cytokines synergize with equally low concentrations of IL-18 to drive rapid and potent NK cell CD25 and IFN-γ expression; IL-18 and IL-2 reciprocally sustain CD25 and IL-18Rα expression in a positive feedback loop; and IL-18 synergizes with FcγRIII (CD16) signaling to augment antibody-dependent cellular cytotoxicity. These data indicate that NK cells can be rapidly activated by very low doses of innate cytokines and that the common γ chain cytokines have overlapping but distinct functions in combination with IL-18. Importantly, synergy between multiple signaling pathways leading to rapid NK cell activation at very low cytokine concentrations has been overlooked in prior studies focusing on single cytokines or simple combinations. Moreover, although the precise common γ chain cytokines available during primary and secondary infections may differ, their synergy with both IL-18 and antigen-antibody immune complexes underscores their contribution to NK cell activation during innate and adaptive responses. IL-18 signaling potentiates NK cell effector function during innate and adaptive immune responses by synergy with IL-2, IL-15, and IL-21 and immune complexes.

  19. ALV-J strain SCAU-HN06 induces innate immune responses in chicken primary monocyte-derived macrophages.

    PubMed

    Feng, Min; Dai, Manman; Cao, Weisheng; Tan, Yan; Li, Zhenhui; Shi, Meiqing; Zhang, Xiquan

    2017-01-01

    Avian leucosis virus subgroup J (ALV-J) can cause lifelong infection and can escape from the host immune defenses in chickens. Since macrophages act as the important defense line against invading pathogens in host innate immunity, we investigated the function and innate immune responses of chicken primary monocyte-derived macrophages (MDM) after ALV-J infection in this study. Our results indicated that ALV-J was stably maintained in MDM cells but that the viral growth rate was significantly lower than that in DF-1 cells. We also found that ALV-J infection significantly increased nitric oxide (NO) production, but had no effect on MDM phagocytic capacity. Interestingly, infection with ALV-J rapidly promoted the expression levels of Myxovirus resistance 1 (Mx) (3 h, 6 h), ISG12 (6 h), and interleukin-1β (IL-1β) (3 h, 12 h) at an early infection stage, whereas it sharply decreased the expression of Mx (24 h, 36 h), ISG12 (36 h), and made little change on IL-1β (24 h, 36 h) production at a late infection stage in MDM cells. Moreover, the protein levels of interferon-β (IFN-β) and interleukin-6 (IL-6) had sharply increased in infected MDM cells from 3 to 36 h post infection (hpi) of ALV-J. And, the protein level of interleukin-10 (IL-10) was dramatically decreased at 36 hpi in MDM cells infected with ALV-J. These results demonstrate that ALV-J can induce host innate immune responses and we hypothesize that macrophages play an important role in host innate immune attack and ALV-J immune escape.

  20. Bilingualism changes children's beliefs about what is innate.

    PubMed

    Byers-Heinlein, Krista; Garcia, Bianca

    2015-03-01

    Young children engage in essentialist reasoning about natural kinds, believing that many traits are innately determined. This study investigated whether personal experience with second language acquisition could alter children's essentialist biases. In a switched-at-birth paradigm, 5- and 6-year-old monolingual and simultaneous bilingual children expected that a baby's native language, an animal's vocalizations, and an animal's physical traits would match those of a birth rather than of an adoptive parent. We predicted that sequential bilingual children, who had been exposed to a new language after age 3, would show greater understanding that languages are learned. Surprisingly, sequential bilinguals showed reduced essentialist beliefs about all traits: they were significantly more likely than other children to believe that human language, animal vocalizations, and animal physical traits would be learned through experience rather than innately endowed. These findings suggest that bilingualism in the preschool years can profoundly change children's essentialist biases.

  1. Crosstalk between microbiota, pathogens and the innate immune responses.

    PubMed

    Günther, Claudia; Josenhans, Christine; Wehkamp, Jan

    2016-08-01

    Research in the last decade has convincingly demonstrated that the microbiota is crucial in order to prime and orchestrate innate and adaptive immune responses of their host and influence barrier function as well as multiple developmental and metabolic parameters of the host. Reciprocally, host reactions and immune responses instruct the composition of the microbiota. This review summarizes recent evidence from experimental and human studies which supports these arms of mutual relationship and crosstalk between host and resident microbiota, with a focus on innate immune responses in the gut, the role of cell death pathways and antimicrobial peptides. We also provide some recent examples on how dysbiosis and pathogens can act in concert to promote intestinal infection, inflammatory pathologies and cancer. The future perspectives of these combined research efforts include the discovery of protective species within the microbiota and specific traits and factors of microbes that weaken or enforce host intestinal homeostasis.

  2. Automated analyses of innate olfactory behaviors in rodents.

    PubMed

    Qiu, Qiang; Scott, Aaron; Scheerer, Hayley; Sapkota, Nirjal; Lee, Daniel K; Ma, Limei; Yu, C Ron

    2014-01-01

    Olfaction based behavioral experiments are important for the investigation of sensory coding, perception, decision making and memory formation. The predominant experimental paradigms employ forced choice operant assays, which require associative learning and reinforced training. Animal performance in these assays not only reflects odor perception but also the confidence in decision making and memory. In this study, we describe a versatile and automated setup, "Poking-Registered Olfactory Behavior Evaluation System" (PROBES), which can be adapted to perform multiple olfactory assays. In addition to forced choice assays, we employ this system to examine animal's innate ability for odor detection, discrimination and preference without elaborate training procedures. These assays provide quantitative measurements of odor discrimination and robust readouts of odor preference. Using PROBES, we find odor detection thresholds are at lower concentrations in naïve animals than those determined by forced choice assays. PROBES-based automated assays provide an efficient way of analyzing innate odor-triggered behaviors.

  3. Regulation of the adaptive immune system by innate lymphoid cells

    PubMed Central

    Hepworth, Matthew R.; Sonnenberg, Gregory F.

    2014-01-01

    Innate lymphoid cells (ILCs) are a group of lymphocytes that promote rapid cytokine-dependent innate immunity, inflammation and tissue repair. In addition, a growing body of evidence suggests ILCs can influence adaptive immune cell responses. During fetal development a subset of ILCs orchestrate the generation and maturation of secondary lymphoid tissues. Following birth, ILCs continue to modulate adaptive immune cell responses indirectly through interactions with stromal cells in lymphoid tissues and epithelial cells at barrier surfaces. In this review we summarize the current understanding of how ILCs modulate the magnitude and quality of adaptive immune cell responses, and in particular focus on recent evidence suggesting that ILCs can also directly regulate CD4+ T cells. Further, we discuss the implications that these pathways may have on human health and disease. PMID:24594491

  4. Innate immune recognition of DNA: A recent history.

    PubMed

    Dempsey, Alan; Bowie, Andrew G

    2015-05-01

    Innate immune DNA sensing underpins many physiological and pathological responses to DNA, including anti-viral immunity to DNA viruses. Although it has been appreciated for many years that cytosolic DNA can evoke a type I interferon response, it is only within the past decade that the cellular mechanisms responsible for such a response have been defined. Here we review the discoveries that led to an appreciation of the existence of cytosolic DNA sensor proteins, and discuss two key such sensors, cGAS and IFI16, in detail. DNA sensors operate via STING, a protein shown to have a central role in controlling altered gene induction in response to DNA in vivo, and as such to be central to a rapidly expanding list of both protective and harmful responses to DNA. We also discuss recent insights into how and when DNA stimulates innate immunity, and highlight current outstanding questions in the DNA sensing field.

  5. Recognition of Streptococcus pneumoniae by the innate immune system.

    PubMed

    Koppe, Uwe; Suttorp, Norbert; Opitz, Bastian

    2012-04-01

    Streptococcus pneumoniae is both a frequent colonizer of the upper respiratory tract and a leading cause of life-threatening infections such as pneumonia, meningitis and sepsis. The innate immune system is critical for the control of colonization and for defence during invasive disease. Initially, pneumococci are recognized by different sensors of the innate immune system called pattern recognition receptors (PRRs), which control most subsequent host defence pathways. These PRRs include the transmembrane Toll-like receptors (TLRs) as well as the cytosolic NOD-like receptors (NLRs) and DNA sensors. Recognition of S. pneumoniae by members of these PRR families regulates the production of inflammatory mediators that orchestrate the following immune response of infected as well as neighbouring non-infected cells, stimulates the recruitment of immune cells such as neutrophils and macrophages, and shapes the adaptive immunity. This review summarizes the current knowledge of the function of different PRRs in S. pneumoniae infection.

  6. Select Drosophila glomeruli mediate innate olfactory attraction and aversion.

    PubMed

    Semmelhack, Julia L; Wang, Jing W

    2009-05-14

    Fruitflies show robust attraction to food odours, which usually excite several glomeruli. To understand how the representation of such odours leads to behaviour, we used genetic tools to dissect the contribution of each activated glomerulus. Apple cider vinegar triggers robust innate attraction at a relatively low concentration, which activates six glomeruli. By silencing individual glomeruli, here we show that the absence of activity in two glomeruli, DM1 and VA2, markedly reduces attraction. Conversely, when each of these two glomeruli was selectively activated, flies showed as robust an attraction to vinegar as wild-type flies. Notably, a higher concentration of vinegar excites an additional glomerulus and is less attractive to flies. We show that activation of the extra glomerulus is necessary and sufficient to mediate the behavioural switch. Together, these results indicate that individual glomeruli, rather than the entire pattern of active glomeruli, mediate innate behavioural output.

  7. Antiviral defense in shrimp: from innate immunity to viral infection.

    PubMed

    Wang, Pei-Hui; Huang, Tianzhi; Zhang, Xiaobo; He, Jian-Guo

    2014-08-01

    The culture of penaeid shrimp is rapidly developing as a major business endeavor worldwide. However, viral diseases have caused huge economic loss in penaeid shrimp culture industries. Knowledge of shrimp innate immunity and antiviral responses has made important progress in recent years, allowing the design of better strategies for the prevention and control of shrimp diseases. In this study, we have updated information on shrimp antiviral immunity and interactions between shrimp hosts and viral pathogens. Current knowledge and recent progress in immune signaling pathways (e.g., Toll/IMD-NF-κB and JAK-STAT signaling pathways), RNAi, phagocytosis, and apoptosis in shrimp antiviral immunity are discussed. The mechanism of viral infection in shrimp hosts and the interactions between viruses and shrimp innate immune systems are also analyzed.

  8. Innate immunity prevents tissue invasion by Entamoeba histolytica.

    PubMed

    Shibayama, Mineko; Rivera-Aguilar, Víctor; Barbosa-Cabrera, Elizabeth; Rojas-Hernández, Saúl; Jarillo-Luna, Adriana; Tsutsumi, Víctor; Pacheco-Yepez, Judith; Campos-Rodríguez, Rafael

    2008-12-01

    Although innate and adaptive immunity both play a role in amoebiasis, the mechanisms involved in the elimination of Entamoeba histolytica are poorly understood. To provide more information about the innate immune mechanisms that may confer protection against invasive amoebiasis, we administered inflammatory substances (bacillus Calmette-Guérin, lipopolysaccharide, complete Freund's adjuvant, or mineral oil) into the peritoneum of hamsters. The animals were then challenged with pathogenic trophozoites of E. histolytica and, after 7 days, the protective host response was analysed. We found that the nonspecific inflammatory response induced in the peritoneum was sufficient to prevent liver invasion by E. histolytica. In vitro experiments showed that the killing of trophozoites was mediated by peritoneal macrophages and a protein of 68 kDa with peroxidase activity.

  9. Innate immunity: actuating the gears of celiac disease pathogenesis.

    PubMed

    Kim, Sangman Michael; Mayassi, Toufic; Jabri, Bana

    2015-06-01

    Celiac disease is a T cell mediated immune disorder characterized by the loss of oral tolerance to dietary gluten and the licensing of intraepithelial lymphocytes to kill intestinal epithelial cells, leading to villous atrophy. Innate immunity plays a critical role in both of these processes and cytokines such as interleukin-15 and interferon-α can modulate innate processes such as polarization of dendritic cells as well as intraepithelial lymphocyte function. These cytokines can be modulated by host microbiota, which can also influence dendritic cell function and intraepithelial lymphocyte homeostasis. We will elaborate on the role of interleukin-15, interferon-α, and the microbiota in modulating the processes that lead to loss of tolerance to gluten and tissue destruction in celiac disease.

  10. Type-2 innate lymphoid cells in asthma and allergy.

    PubMed

    McKenzie, Andrew N J

    2014-12-01

    Type-2 innate lymphoid cells (ILC2) belong to an expanding family of innate lymphocytes that provide a potent source of immune effector cytokines at the initiation of immune responses. ILC2 arise, under the control of the transcription factors RORα and GATA3, from lymphoid progenitors in the bone marrow, to secrete type-2 cytokines including IL-5 and IL-13. Using experimental models, ILC2 have been implicated in allergic diseases, such as asthma and atopic dermatitis, but also in metabolic homeostasis. Furthermore, recent reports have indicated that ILC2 not only play roles at the initiation of type-2 immunity but can also contribute to chronic pathology, such as fibrosis, and can impact on the priming of the adaptive T-cell response. The identification of ILC2 in patients with allergic dermatitis and allergic rhinitis indicates that these cells may represent new therapeutic targets.

  11. Commensal bacteria calibrate the activation threshold of innate antiviral immunity.

    PubMed

    Abt, Michael C; Osborne, Lisa C; Monticelli, Laurel A; Doering, Travis A; Alenghat, Theresa; Sonnenberg, Gregory F; Paley, Michael A; Antenus, Marcelo; Williams, Katie L; Erikson, Jan; Wherry, E John; Artis, David

    2012-07-27

    Signals from commensal bacteria can influence immune cell development and susceptibility to infectious or inflammatory diseases. However, the mechanisms by which commensal bacteria regulate protective immunity after exposure to systemic pathogens remain poorly understood. Here, we demonstrate that antibiotic-treated (ABX) mice exhibit impaired innate and adaptive antiviral immune responses and substantially delayed viral clearance after exposure to systemic LCMV or mucosal influenza virus. Furthermore, ABX mice exhibited severe bronchiole epithelial degeneration and increased host mortality after influenza virus infection. Genome-wide transcriptional profiling of macrophages isolated from ABX mice revealed decreased expression of genes associated with antiviral immunity. Moreover, macrophages from ABX mice exhibited defective responses to type I and type II IFNs and impaired capacity to limit viral replication. Collectively, these data indicate that commensal-derived signals provide tonic immune stimulation that establishes the activation threshold of the innate immune system required for optimal antiviral immunity.

  12. Mechanisms of innate immunity in C. elegans epidermis

    PubMed Central

    Taffoni, Clara; Pujol, Nathalie

    2015-01-01

    The roundworm C. elegans has been successfully used for more than 50 y as a genetically tractable invertebrate model in diverse biological fields such as neurobiology, development and interactions. C. elegans feeds on bacteria and can be naturally infected by a wide range of microorganisms, including viruses, bacteria and fungi. Most of these pathogens infect C. elegans through its gut, but some have developed ways to infect the epidermis. In this review, we will mainly focus on epidermal innate immunity, in particular the signaling pathways and effectors activated upon wounding and fungal infection that serve to protect the host. We will discuss the parallels that exist between epidermal innate immune responses in nematodes and mammals. PMID:26716073

  13. Osteopontin Bridging Innate and Adaptive Immunity in Autoimmune Diseases

    PubMed Central

    Raineri, Davide; Boggio, Elena; Favero, Francesco; Soluri, Maria Felicia

    2016-01-01

    Osteopontin (OPN) regulates the immune response at multiple levels. Physiologically, it regulates the host response to infections by driving T helper (Th) polarization and acting on both innate and adaptive immunity; pathologically, it contributes to the development of immune-mediated and inflammatory diseases. In some cases, the mechanisms of these effects have been described, but many aspects of the OPN function remain elusive. This is in part ascribable to the fact that OPN is a complex molecule with several posttranslational modifications and it may act as either an immobilized protein of the extracellular matrix or a soluble cytokine or an intracytoplasmic molecule by binding to a wide variety of molecules including crystals of calcium phosphate, several cell surface receptors, and intracytoplasmic molecules. This review describes the OPN structure, isoforms, and functions and its role in regulating the crosstalk between innate and adaptive immunity in autoimmune diseases. PMID:28097158

  14. Migration and Tissue Tropism of Innate Lymphoid Cells

    PubMed Central

    Kim, Chang H.; Hashimoto-Hill, Seika; Kim, Myunghoo

    2016-01-01

    Innate lymphoid cell (ILCs) subsets differentially populate various barrier and non-barrier tissues, where they play important roles in tissue homeostasis and tissue-specific responses to pathogen attack. Recent findings have provided insight into the molecular mechanisms that guide ILC migration into peripheral tissues, revealing common features among different ILC subsets as well as important distinctions. Recent studies have also highlighted the impact of tissue-specific cues on ILC migration, and the importance of the local immunological milieu. We review these findings here and discuss how the migratory patterns and tissue tropism of different ILC subsets relate to the development and differentiation of these cells, and to ILC-mediated tissue-specific regulation of innate and adaptive immune responses. In this context we outline open questions and important areas of future research. PMID:26708278

  15. Innate spatial-temporal reasoning and the identification of genius.

    PubMed

    Peterson, Matthew R; Balzarini, Doreen; Bodner, Mark; Jones, Edward G; Phillips, Tiffany; Richardson, Debra; Shaw, Gordon L

    2004-01-01

    The teaching of mathematics is invariably language-based, but spatial-temporal (ST) reasoning (making a mental image and thinking ahead in space and time) is crucial to the understanding of math. Here we report that Big Seed, a demanding ST video game, based upon the mathematics of knot theory and previously applied to understanding DNA structure and function, can be used to reveal innate ST reasoning. Big Seed studies with middle and elementary school children provide strong evidence that ST reasoning ability is not only innate but far exceeds optimistic expectations based on age, the percentage of children achieving exceptional ST performance in less than 7 h of training, and retention of ability. A third grader has been identified as a genius (functionally defined) in ST performance. Big Seed may be used for training and assessing 'creativity' (functionally defined) and ST reasoning as well as discovering genius.

  16. TLR signaling: an emerging bridge from innate immunity to atherogenesis.

    PubMed

    Michelsen, Kathrin S; Doherty, Terence M; Shah, Prediman K; Arditi, Moshe

    2004-11-15

    Chronic inflammation and disordered lipid metabolism represent hallmarks of atherosclerosis. Considerable evidence suggests that innate immune defense mechanisms might interact with proinflammatory pathways and contribute to development of arterial plaques. The preponderance of such evidence has been indirect clinical and epidemiologic studies, with some support from experimental animal models of atherosclerosis. However, recent data now directly implicate signaling by TLR4 in the pathogenesis of atherosclerosis, establishing a key link between atherosclerosis and defense against both foreign pathogens and endogenously generated inflammatory ligands. In this study, we briefly review these and closely related studies, highlighting areas that should provide fertile ground for future studies aimed at a more comprehensive understanding of the interplay between innate immune defense mechanisms, atherosclerosis, and related vascular disorders.

  17. Commensal Bacteria Calibrate the Activation Threshold of Innate Antiviral Immunity

    PubMed Central

    Abt, Michael C.; Osborne, Lisa C.; Monticelli, Laurel A.; Doering, Travis A.; Alenghat, Theresa; Sonnenberg, Gregory F.; Paley, Michael A.; Antenus, Marcelo; Williams, Katie L.; Erikson, Jan; Wherry, E. John; Artis, David

    2013-01-01

    SUMMARY Signals from commensal bacteria can influence immune cell development and susceptibility to infectious or inflammatory diseases. However, the mechanisms by which commensal bacteria regulate protective immunity after exposure to systemic pathogens remain poorly understood. Here, we demonstrate that antibiotic-treated (ABX) mice exhibit impaired innate and adaptive antiviral immune responses and substantially delayed viral clearance after exposure to systemic LCMV or mucosal influenza virus. Furthermore, ABX mice exhibited severe bronchiole epithelial degeneration and increased host mortality after influenza virus infection. Genome-wide transcriptional profiling of macrophages isolated from ABX mice revealed decreased expression of genes associated with antiviral immunity. Moreover, macrophages from ABX mice exhibited defective responses to type I and type II IFNs and impaired capacity to limit viral replication. Collectively, these data indicate that commensal-derived signals provide tonic immune stimulation that establishes the activation threshold of the innate immune system required for optimal antiviral immunity. PMID:22705104

  18. Exactly conservative integrators

    SciTech Connect

    Shadwick, B.A.; Bowman, J.C.; Morrison, P.J.

    1995-07-19

    Traditional numerical discretizations of conservative systems generically yield an artificial secular drift of any nonlinear invariants. In this work we present an explicit nontraditional algorithm that exactly conserves invariants. We illustrate the general method by applying it to the Three-Wave truncation of the Euler equations, the Volterra-Lotka predator-prey model, and the Kepler problem. We discuss our method in the context of symplectic (phase space conserving) integration methods as well as nonsymplectic conservative methods. We comment on the application of our method to general conservative systems.

  19. Conservation: Toward firmer ground

    NASA Technical Reports Server (NTRS)

    1975-01-01

    The following aspects of energy conservation were reviewed in order to place the problems in proper perspective: history and goals, conservation accounting-criteria, and a method to overcome obstacles. The effect of changing prices and available supplies of energy sources and their causes on consumption levels during the last few decades were described. Some examples of attainable conservation goals were listed and justified. A number of specific criteria applicable to conservation accounting were given. Finally, a discussion was presented to relate together the following aspects of energy conservation: widespread impact, involvement of government, industry, politics, moral and ethical aspects, urgency and time element.

  20. Molecular insights on the cerebral innate immune system.

    PubMed

    Rivest, Serge

    2003-02-01

    All species need an immediate reply to the microbial pathogens that is part of an effective immune response and is essential for the survival of most organisms. This reply is known as the innate immune response and is characterized by the de novo production of mediators that either kill the microbes directly or activate phagocytic cells to ingest and kill them. The innate immune response can be driven through specific recognition systems, the best example being an interaction between the endotoxin lipopolysaccharide (LPS) and its receptors CD14 and Toll-like receptor 4 (TLR4). For a long time, the brain was considered to be a privileged organ from an immunological point of view, owing to its inability to mount an immune response and process antigens. Although this is partly true, the CNS shows a well-organized innate immune reaction in response to systemic bacterial infection and cerebral injury. The CD14 and TLR4 receptors are constitutively expressed in the circumventricular organs (CVOs), choroid plexus and leptomeninges. Circulating LPS is able to cause a rapid transcriptional activation of genes encoding CD14 and TLR2, as well as a wide variety of pro-inflammatory molecules in CVOs. A delayed response to LPS takes place in cells located at boundaries of the CVOs and in microglia across the CNS. Therefore, without having direct access to the brain parenchyma, pathogens have the ability to trigger an innate immune reaction throughout cerebral tissue. This review presents evidence supporting the existence of such a system in the brain, which is finely regulated at the transcription level. Transient activation of this system is not harmful toward neuronal elements.